HIV protease inhibiting compounds

ABSTRACT

A compound of the formula 
                         
is disclosed as an HIV protease inhibitor. Methods and compositions for inhibiting an HIV infection are also disclosed.

This application claims priority to U.S. patent application Ser. No.60/528,974, filed Dec. 11, 2003 and is incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to novel compounds and a composition and amethod for inhibiting human immunodeficiency virus (HIV) protease, acomposition and method for inhibiting or treating an HIV infection,processes for making the compounds and synthetic intermediates employedin the processes.

BACKGROUND OF THE INVENTION

The genome of the human immunodeficiency virus (HIV) encodes a proteasethat is responsible for the proteolytic processing of one or morepolyprotein precursors such as the pol and gag gene products. HIVprotease processes the gag precursor into core proteins and alsoprocesses the pol precursor into reverse transcriptase and protease.

The correct processing of the precursor polyproteins by HIV protease isnecessary for the assembly of infectious virions. Therefore, inhibitionof HIV protease provides a useful target for development of therapeuticagents for treatment of HIV infection.

In recent years, inhibitors of HIV protease have become an importantclass of therapeutic agents for inhibition and treatment of HIVinfection in humans. HIV protease inhibitors are especially effectivewhen administered in combination with other classes of HIV therapeuticagents, especially inhibitors of HIV reverse transcriptase, in“cocktails” of HIV therapeutic agents.

At the present time, the HIV protease inhibitors saquinavir, ritonavir,indinavir, nelfinavir, amprenavir, lopinavir/ritonavir, fosamprenavir,and atazanavir have been approved in the U.S. for treatment of HIVinfection. There is a continuing need for improved HIV proteaseinhibitors that are very potent, that have reduced side-effects and thatare effective against resistant strains of HIV.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula (I)

or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, wherein:

-   A is

-   X is O, S or NH;-   Y is O, S or NH;-   B is H or —CH₂R⁹;-   L is —C(═O), —C(═S), —C(═NH) or —S(O)₂;-   R^(A) is —N(H)C(O)R⁸, —O(R_(a)), —OC(O)OR_(a), —NR_(a)R_(b),    —N(R_(b))S(O)₂R_(a), —N(R_(b))alkylN(R_(b))S(O)₂R_(a),    —N(R_(b))alkylN(R_(b))C(O)OR_(a),    —N(R_(b))alkylN(R_(b))C(O)NR_(a)R_(b), -alkylSR_(a), -alkylS(O)R_(a)    or -alkylS(O)_(a) or -alkylS(O)₂R_(a);-   R¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,    heterocycle, aryl or heteroaryl; wherein each R¹ is substituted with    0, 1 or 2 substituents independently selected from the group    consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl,    hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),    —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂, and    R^(1a);-   R^(1a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(1a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R² is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,    heterocycle, aryl or heteroaryl; wherein each R² is substituted with    0, 1 or 2 substituents independently selected from the group    consisting of halo, —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a),    —NR_(a)R_(b), —NR_(b)C(O)R_(a), —N(R_(b))C(O)OR_(a),    —N(R_(a))C(═N)NR_(a)R_(b), —N(R_(a))C(O)NR_(a)R_(b),    —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(2a);-   R^(2a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(2a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R³ is alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, -alkylOR_(a),    -alkylSR_(a), -alkylSOR_(a), -alkylSO₂R_(a), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)OR_(a),    -alkylN(R_(a))C(═N)NR_(a)R_(b), -alkylN(R_(a))C(O)NR_(a)R_(b),    -alkylC(O)NR_(a)R_(b), -alkylC(O)OR_(a), cycloalkyl,    cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle,    heterocyclealkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;    wherein the cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl,    cycloalkyl moiety of the cycloalkylalkyl, cycloalkenyl moiety of the    cycloalkenylalkyl, heterocycle moiety of the heterocyclealkyl,    heteroaryl moiety of the heteroarylalkyl and the aryl moiety of the    arylalkyl are independently substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and    R^(3a);-   R^(3a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(3a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    oxo, alkyl, alkenyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), and -alkylC(O)N(alkyl)₂;-   R⁴ is H and R⁵ is OR¹⁶; or-   R⁵ is H and R⁴ is OR¹⁶; or-   R⁴ and R⁵ are —OR¹⁶;-   R⁶ is alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, -alkylOR_(a),    -alkylSR_(a), -alkylSOR_(a), -alkylSO₂R_(a), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)OR_(a),    -alkylN(R_(a))C(═N)NR_(a)R_(b), -alkylN(R_(a))C(O)NR_(a)R_(b),    -alkylC(O)NR_(a)R_(b), -alkylC(O)OR_(a), cycloalkyl,    cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle,    heterocyclealkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;    wherein the cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl,    cycloalkyl moiety of the cycloalkylalkyl, cycloalkenyl moiety of the    cycloalkenylalkyl, heterocycle moiety of the heterocyclealkyl,    heteroaryl moiety of the heteroarylalkyl and the aryl moiety of the    arylalkyl are independently substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and    R^(6a);-   R^(6a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(6a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    oxo, alkyl, alkenyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), and -alkylC(O)N(alkyl)₂;-   R⁷ is —N(R_(b))C(O)OR_(a), alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, heterocycle, aryl or heteroaryl; wherein the alkyl,    alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl and    heteroaryl are independently substituted with 0, 1 or 2 substituents    independently selected from the group consisting of halo, —OR_(a),    —OC(O)R_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —NR_(a)R_(b),    —N(R_(b))C(O)R_(a), —N(R_(b))C(O)OR_(a), —N(R_(a))C(═N)NR_(a)R_(b),    —N(R_(a))C(O)NR_(a)R_(b), —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(7a);-   R^(7a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(7a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R⁸ is —OR_(a), —NR_(a)R_(b), —N(R_(b))C(O)OR_(a), -alkylOR_(a),    -alkylOC(O)R_(a), or —O-alkylC(O)R_(a);-   R⁹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R⁹ is substituted with 0, 1,    2 or 3 substituents independently selected from the group consisting    of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro, oxo,    —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))SO₂R_(a),    —N(R_(b))SO₂NR_(a)R_(b), —N(R_(b))C(O)NR_(a)R_(b),    —N(R_(b))C(O)OR_(a), —C(O)R_(a), —C(O)NR_(a)R_(b), —C(O)OR_(a),    haloalkyl, nitroalkyl, cyanoalkyl, formylalkyl, -alkylOR_(a),    -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)OR_(a), -alkylN(R_(b))SO₂NR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkylC(O)R_(a),    -alkylC(O)NR_(a)R_(b) and R^(9a);-   R^(9a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(9a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹⁰ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R¹⁰ is substituted with 0,    1, 2 or 3 substituents independently selected from the group    consisting of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro,    oxo, —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))SO₂R_(a),    —N(R_(b))SO₂NR_(a)R_(b), —N(R_(b))C(O)NR_(a)R_(b),    —N(R_(b))C(O)OR_(a), —C(O)R_(a), —C(O)NR_(a)R_(b), —C(O)OR_(a),    haloalkyl, nitroalkyl, cynaoalkyl, formylalkyl, -alkylOR_(a),    -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)OR_(a), -alkylN(R_(b))SO₂NR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkylC(O)R_(a),    -alkylC(O)NR_(a)R_(b) and R^(10a);-   R^(10a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or    heteroaryl; wherein each R^(10a) is substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R¹¹ is substituted with 0,    1, 2 or 3 substituents independently selected from the group    consisting of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro,    oxo, —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))SO₂R_(a),    —N(R_(b))SO₂NR_(a)R_(b), —N(R_(b))C(O)NR_(a)R_(b),    —N(R_(b))C(O)OR_(a), —C(O)R_(a), —C(O)NR_(a)R_(b), —C(O)OR_(a),    haloalkyl, nitroalkyl, cynaoalkyl, formylalkyl, -alkylOR_(a),    -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)OR_(a), -alkylN(R_(b))SO₂NR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkylC(O)R_(a),    -alkylC(O)NR_(a)R_(b) and R^(11a);-   R^(11a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or    heteroaryl; wherein each R^(11a) is substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R¹² is alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl or    cycloalkenylalkyl; wherein each R¹² is substituted with 0, 1 or 2    substituents independently selected from the group consisting of    hydroxy, alkoxy and halo;-   R¹³ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R¹³ is substituted with 0,    1, 2 or 3 substituents independently selected from the group    consisting of alkyl, alkenyl, alkynyl, cyano, halo, nitro, oxo,    —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a),—N(R_(b))C(O)OR_(a),    C(O)NR_(a)R_(b), —C(O)OR_(a), haloalkyl, nitroalkyl, cynaoalkyl,    -alkylOR_(a), -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkyl-C(O)NR_(a)R_(b) and    R^(13a);-   R^(13a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or    heteroaryl; wherein each R^(13a) is substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹⁴ is —OR_(a), -alkylOR_(a), aryl, heteroaryl or heterocycle;    wherein the aryl, heteroaryl and heterocycle are independently    substituted with 0, 1, 2, 3 or 4 substituents independently selected    from the group consisting of cyano, halo, nitro, oxo, alkyl,    alkenyl, alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂,    —SH, —S(alkyl), —SO₂(alkyl), —S(O)₂NR_(a)R_(b), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹⁶ is hydrogen or R¹⁵;-   R¹⁵ is

-   R₁₀₃ is C(R₁₀₅)₂, O or —N(R₁₀₅);-   R₁₀₄ is hydrogen, alkyl, haloalkyl, alkoxycarbonyl, aminocarbonyl,    alkylaminocarbonyl or dialkylaminocarbonyl,    each M is independently selected from the group consisting of H,    —N(R₁₀₅)₂, alkyl, alkenyl, and-   R₁₀₆; wherein 1 to 4 —CH₂ radicals of the alkyl or alkenyl, other    than the —CH₂ radical that is bound to Z, is optionally replaced by    a heteroatom group selected from the group consisting of O, S, S(O),    SO₂ and N(R₁₀₅); and wherein any hydrogen in said alkyl, alkenyl or    R₁₀₆ is optionally replaced with a substituent selected from the    group consisting of oxo, —OR₁₀₅, —R₁₀₅, —N(R₁₀₅)₂, —CN, —C(O)OR₁₀₅,    —C(O)N(R₁₀₅)₂, —SO₂N(R₁₀₅), —N(R₁₀₅)C(O)R₁₀₅, —C(O)R —S(O)R₁₀₅,    —SO₂R₁₀₅, —OCF₃, —SR₁₀₆, —SOR₁₀₆, —SO₂R₁₀₆, —N(R₁₀₅)SO₂R₁₀₅, halo,    —CF₃, NO₂ and phenyl; provided that when M is —N(R₁₀₅)₂, Z₁ and Z₂    are CH₂;-   Z₁ is CH₂, O, S, —N(R₁₀₅), or, when M is absent, H;-   Z₂ is CH₂, O, S or —N(R₁₀₅);-   Q is O or S;-   W is P or S; wherein when W is S, Z₁ and Z₂ are not S;-   M′ is H, alkyl, alkenyl or R₁₀₆; wherein 1 to 4 —CH₂ radicals of the    alkyl or alkenyl is optionally replaced by a heteroatom group    selected from O, S, S(O), SO₂, or N(R₁₀₅); and wherein any hydrogen    in said alkyl, alkenyl or R₁₀₆ is optionally replaced with a    substituent selected from the group consisting of oxo, —OR₁₀₅,    —R₁₀₅, —N(R₁₀₅)₂, —CN, —C(O)OR₁₀₅, —C(O)N(R₁₀₅)₂, —SO₂N(R₁₀₅),    —N(R₁₀₅)C(O)R₁₀₅, —C(O)R₁₀₅, —SR₁₀₅, —S(O)R₁₀₅, —SO₂R₁₀₅, —OCF₃,    —SR₁₀₆, —SOR₁₀₆, —SO₂R₁₀₆, —N(R₁₀₅)SO₂R₁₀₅, halo, —CF₃ and NO₂;-   R₁₀₆ is a monocyclic or bicyclic ring system selected from the group    consisting of aryl, cycloalkyl, cycloalkenyl heteroaryl and    heterocycle; wherein any of said heteroaryl and heterocycle ring    systems contains one or more heteroatoms selected from the group    consisting of O, N, S, SO, SO₂ and N(R₁₀₅); and wherein any of said    ring system is substituted with 0, 1, 2, 3, 4, 5 or 6 substituents    selected from the group consisting of hydroxy, alkyl, alkoxy, and    —OC(O)alkyl;    each R₁₀₅ is independently selected from the group consisting of H    or alkyl; wherein said alkyl is optionally substituted with a ring    system selected from the group consisting of aryl, cycloalkyl,    cycloalkenyl, heteroaryl and heterocycle; wherein any of said    heteroaryl and heterocycle ring systems contains one or more    heteroatoms selected from the group consisting of O, N, S, SO, SO₂,    and N(R₁₀₅); and wherein any one of said ring systems is substituted    with 0, 1, 2, 3 or 4 substituents selected from the group consisting    of oxo, —OR₁₀₅, —R₁₀₅, —N(R₁₀₅)₂, —N(R₁₀₅)C(O)R₁₀₅, —CN, —C(O)OR₁₀₅,    —C(O)N(R₁₀₅)₂, halo and —CF₃;    each R₁₀₇ and R₁₀₈ are independently selected from the group    consisting of hydrogen and alkyl;-   q is 0 or 1;-   m is 0 or 1;-   m′ is 0 or 1;-   m″is 0 or 1;-   r is 0, 1, 2, 3 or 4;-   t is 0 or 1;-   R_(a) and R_(b) at each occurrence are independently selected from    the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    cycloalkyl, aryl, heteroaryl and heterocycle; wherein each R_(a) and    R_(b), at each occurrence, is independently substituted with 0, 1, 2    or 3 substituents independently selected from the group consisting    of cyano, nitro, halo, oxo, alkyl, alkenyl, alkynyl, hydroxy,    alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and R_(c);    alternatively, R_(a) and R_(b), together with the nitrogen atom to    which they are attached, form a ring selected from the group    consisting of heteroaryl and heterocycle; wherein each of the    heteroaryl and heterocycle is independently substituted with 0, 1, 2    or 3 substituents independently selected from the group consisting    of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo,    hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),    —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, formylalkyl,    nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH₂,    -alkylN(H)(alkyl), -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂,    -alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH,    -alkylC(O)Oalkyl, -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl),    -alkylC(O)N(alkyl)₂ and R_(a);-   R_(c) is aryl, heteroaryl or heterocycle; wherein each R_(c) is    independently substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of halo, nitro,    oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkyl-NH₂, -alkyl-N(H)(alkyl), -alkyl-N(alkyl)₂,    -alkyl-N(H)C(O)NH₂, -alkyl-N(H)C(O)N(H)(alkyl),    -alkyl-N(H)C(O)N(alkyl)₂, -alkyl-C(O)OH, -alkyl-C(O)Oalkyl,    -alkyl-C(O)NH₂, -alkyl-C(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂; and    n is 1 or 2.

The present invention also provides the processes of making a compoundof the present invention and intermediates employed in the processes.

The present invention further provides a pharmaceutical compositioncomprising a therapeutically effective amount of a compound orcombination of compounds of the present invention, or a pharmaceuticallyacceptable salt form, stereoisomer, ester, salt of an ester, prodrug,salt of a prodrug, or combination thereof, and a pharmaceuticallyacceptable carrier.

The present invention yet further provides a pharmaceutical compositioncomprising a therapeutically effective amount of a compound orcombination of compounds of the present invention, or a pharmaceuticallyacceptable salt form, stereoisomer, ester, salt of an ester, prodrug,salt of a prodrug, or combination thereof, and one, two, three, four,five or six agents selected from the group consisting of a second HIVprotease inhibitor, a HIV reverse transcriptase inhibitor, an HIVentry/fusion inhibitor, an HIV integrase inhibitor and an HIVbudding/maturation inhibitor, and a pharmaceutically acceptable carrier.

The present invention also provides a pharmaceutical compositioncomprising a therapeutically effective amount of a compound orcombination of compounds of the present invention, or a pharmaceuticallyacceptable salt form, stereoisomer, ester, salt of an ester, prodrug,salt of a prodrug, or combination thereof, ritonavir or apharmaceutically acceptable salt form or prodrug thereof, and apharmaceutically acceptable carrier.

The present invention still further provides a method of inhibiting thereplication of an HIV virus comprising contacting said virus with atherapeutically effective amount of a compound or combination ofcompounds of the present invention, or a pharmaceutically acceptablesalt form, stereoisomer, ester, salt of an ester, prodrug, salt of aprodrug, or combination thereof, and a pharmaceutically acceptablecarrier.

The present invention still further provides a method of inhibiting thereplication of an HIV virus comprising contacting said virus with thepharmaceutical composition of the present invention.

The present invention further provides a method of inhibiting HIVprotease comprising contacting said HIV protease with a therapeuticallyeffective amount of a compound or combination of compounds of thepresent invention, or a pharmaceutically acceptable salt form,stereoisomer, ester, salt of an ester, prodrug, salt of a prodrug, orcombination thereof, and a pharmaceutically acceptable carrier.

The present invention further provides a method of inhibiting HIVprotease comprising contacting said HIV protease with the pharmaceuticalcomposition of the present invention.

The present invention also provides a method of treating or preventingan HIV infection comprising administering to a patient in need of suchtreatment a therapeutically effective amount of a compound orcombination of compounds of the present invention, or a pharmaceuticallyacceptable salt form, stereoisomer, ester, salt of an ester, prodrug,salt of a prodrug, or combination thereof, and a pharmaceuticallyacceptable carrier.

The present invention also provides a method of treating or preventingan HIV infection comprising administering to a patient in need of suchtreatment the pharmaceutical composition of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

As used in the present specification the following terms have themeanings indicated:

As used herein, the singular forms “a”, “an”, and “the” may includeplural reference unless the context clearly dictates otherwise.

The term “activated carboxylic acid group” as used herein refers to acidhalides such as acid chlorides and also refers to activated esterderivatives including, but not limited to, formic and acetic acidderived anhydrides, anhydrides derived from alkoxycarbonyl halides suchas isobutyloxycarbonylchloride and the like, anhydrides derived fromreaction of the carboxylic acid with N,N′-carbonyldiimidazole and thelike, N-hydroxysuccinimide derived esters, N-hydroxyphthalimide derivedesters, N-hydroxybenzotriazole derived esters,N-hydroxy-5-norbornene-2,3-dicarboximide derived esters,2,4,5-trichlorophenol derived esters, p-nitrophenol derived esters,phenol derived esters, pentachlorophenol derived esters,8-hydroxyquinoline derived esters and the like.

The term “alkanoyl” as used herein refers to an alkyl group attached tothe parent molecular moiety through a carbonyl group. Representativeexamples of alkanoyl include, but not limited to, methylcarbonyl,ethylcarbonyl and tert-butylcarbonyl.

The term “alkyl,” as used herein, refers to a group derived from astraight or branched chain saturated hydrocarbon containing 1, 2, 3, 4,5, 6, 7, 8, 9 or 10 carbon atoms. Representative examples of alkylgroups include, but not limited to, r-propyl, butyl, methyl,1-methylpropyl, 2-methylbutyl, 3-methylpropyl, tert-butyl,1,1-dimethylethyl, 1-methylethyl and isopropyl (1-methylethyl).

The term “alkylamino” as used herein refers to —N(H)R⁹⁰ wherein R⁹⁰ isalkyl.

The term “alkylaminocarbonyl” as used herein refers to an alkylaminogroup attached to the parent molecular moiety through a carbonyl group.

The term “alkenyl,” as used herein, refers to a straight or branchedchain group of 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms containing atleast one carbon-carbon double bond. Representative examples of alkenylgroups include, but not limited to, allyl, propenyl and3-methyl-2-butenyl.

The term “alkynyl,” as used herein, refers to a straight or branchedchain hydrocarbon of 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atomscontaining at least one carbon-carbon triple bond. Representativeexamples of alkynyl groups include, but not limited to, ethynyl,2-methyl-3-butynyl and 3-pentynyl.

The term “alkoxy,” as used herein, refers to an alkyl group attached tothe parent molecular moiety through an oxygen atom. Representativeexamples of alkoxy groups include, but not limited to, tert-butoxy,methoxy, 2-methoxy-1,1-dimethylethyl, 2-ethoxy-1,1-dimethylethyl andisopropoxy.

The term “alkoxyalkyl,” as used herein, refers to an alkyl groupsubstituted by at least one alkoxy group.

The term “alkoxycarbonyl,” as used herein, refers to an alkoxy groupattached to the parent molecular moiety through a carbonyl group.Representative examples of alkoxycarbonyl groups include, but notlimited to, tert-butoxycarbonyl, ethoxycarbonyl and methoxycarbonyl.

The term “aryl” as used herein, refers to a phenyl group, or a bicyclicor tricyclic hydrocarbon fused ring systems wherein one or more of therings is a phenyl group. Bicyclic fused ring systems have a phenyl groupfused to a monocyclic cycloalkenyl group, as defined herein, amonocyclic cycloalkyl group, as defined herein, or another phenyl group.Tricyclic fused ring systems are exemplified by a bicyclic fused ringsystem fused to a monocyclic cycloalkenyl group, as defined herein, amonocyclic cycloalkyl group, as defined herein, or another phenyl group.Representative examples of aryl groups include, but not limited to,anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl andtetrahydronaphthyl. The aryl groups of the present invention can besubstituted or unsubstituted, and are connected to the parent molecularmoiety through any substitutable carbon atom of the group.

The term “arylalkyl”, as used herein, refers to an aryl group, asdefined herein, attached to the parent molecular moiety through an alkylgroup. Representative examples of arylalkyl groups include, but are notlimited to, phenylmethyl (benzyl), naphthylmethyl, phenylethyl,tetrahydronaphthylmethyl and naphthylethyl.

The term “carbonyl” as used herein, refers to —C(═O).

The term “cyano,” as used herein, refers to —CN.

The term “cyanoalkyl,” as used herein, refers to a cyano group attachedto the parent molecular moiety through an alkyl group.

The term “cycloalkenyl,” as used herein, refers to a non-aromatic,partially unsaturated, monocyclic, bicyclic or tricyclic hydrocarbonring system, having three to fourteen carbon atoms, zero heteroatom andone, two, three or four double bonds. Representative examples ofcycloalkenyl groups include, but not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexenyl, octahydronaphthalenyl andnorbornylenyl. The cycloalkenyl groups of the present invention can beunsubstituted or substituted, and are attached to the parent molecularmoiety through any substitutable carbon atom of the group.

The term “cycloalkenylalkyl”, as used herein, refers to a cycloalkenylgroup attached to the parent molecular moiety through an alkyl group.

The term “cycloalkyl,” as used herein, refers to a saturated monocyclic,bicyclic, or tricyclic hydrocarbon ring system having three to fourteencarbon atoms and zero heteroatom. Representative examples of cycloalkylgroups include, but not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[3.1.1]heptyl,6,6-dimethylbcyclo[3.1.1]heptyl and adamantyl like. The cycloalkylgroups of the present invention can be unsubstituted or substituted, andare connected to the parent molecula moiety through any substitutablecarbon atom of the group.

The term “cycloalkylalkyl”, as used herein, refers to a cycloalkyl groupattached to the parent molecular moiety through an alkyl group.

The term “dialkylamino” as used herein refers to —NR⁹⁰R⁹¹, wherein R⁹⁰and R⁹¹ are alkyls.

The term “dialkylamninocarbonyl” as used herein refers to a dialkylaminogroup as defined herein, appended to the parent molecular moiety througha carbonyl group.

The terms “halo,” and “halogen” as used herein, refer to F, Cl, Br, andI.

The term “haloalkoxy,” as used herein, refers to a haloalkyl groupattached to the parent molecular moiety through an oxygen atom.

The term “haloalkenyl” as used herein, refers to an alkenyl groupsubstituted by one, two, three or four halogen atoms.

The term “haloalkyl” as used herein, refers to an alkyl groupsubstituted by one, two, three, or four halogen atoms. Examples ofhaloalkyl include, but are not limited to, trifluoromethyl,fluoromethyl, difluoromethyl, 1-fluoroethyl, 1,2-difluoroethyl, and1,2,3-trifluoroethyl.

The term “heteroaryl” as used herein, refers to an aromatic five- orsix-membered ring where at least one atom is selected from the groupconsisting of N, O, and S, and the remaining atoms are carbon. The term“heteroaryl” also includes bicyclic systems where a heteroaryl ring isfused to a phenyl group, a monocyclic cycloalkyl group, as definedherein, a monocyclic cycloalkenyl group, as defined herein, a monocyclicheterocycle group, as defined herein, or an additional monocyclicheteroaryl group. The term “heteroaryl” also includes tricyclic systemswhere a bicyclic system is fused to a phenyl group, a monocycliccycloalkyl group, as defined herein, a monocyclic cycloalkenyl group, asdefined herein, a monocyclic heterocycle group, as defined herein, or anadditional monocyclic heteroaryl group. Representative examples ofheteroaryl groups include, but not limited to, benzothienyl,benzoxazolyl, benzimidazolyl, benzoxadiazolyl, dibenzofuranyl,dihydrobenzothiazolyl, furanyl, imidazolyl, imidazopyridyl, indazolyl,indolyl, isoindolyl, isoxazolyl, isoquinolinyl, isothiazolyl,oxadiazolyl, oxazolyl, thiazolyl, thienopyridinyl, thienyl, triazolyl,thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,pyrazolyl, pyrrolyl, quinolinyl, tetrahydroquinolinyl and triazinyl. Theheteroaryl groups of the present invention can be substituted orunsubstituted, and are connected to the parent molecular moiety throughany substitutable carbon or nitrogen atom in the groups. In addition,the nitrogen heteroatoms may or may not be quaternized or oxidized tothe N-oxide. Also, the nitrogen containing rings may or may not beN-protected.

The term “heteroarylalkyl” as used herein, refers to an heteroaryl groupas defined herein, appended to the parent molecular moiety through analkyl group as defined herein.

The term “heterocycle” as used herein, refers to cyclic, non-aromatic,saturated or partially unsaturated, three, four, five-, six-, orseven-membered rings containing at least one atom selected from thegroup consisting of oxygen, nitrogen, and sulfur. The term “heterocycle”also includes bicyclic systems where a heterocycle ring is fused to aphenyl group, a monocyclic cycloalkenyl group, as defined herein, amonocyclic cycloalkyl group, as defined herein, or an additionalmonocyclic heterocycle group. The term “heterocycle” also includestricyclic systems where a bicyclic system is fused to a phenyl group, amonocyclic cycloalkenyl group, as defined herein, a monocycliccycloalkyl group, as defined herein, or an additional monocyclicheterocycle group. The heterocycle groups of the invention aresubstituted or unsubstituted, and are connected to the parent molecularmoiety through any substitutable carbon or nitrogen atom in the groups.Representative examples of heterocycle groups include, but not limitedto, benzoxazinyl, dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl,1,4-dioxanyl, 1,3-dioxolanyl, hexahydrofurofuranyl, isoindolinyl,morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl,piperidinyl, thiomorpholinyl and tetrahydropyranyl. The nitrogenheteroatoms may or may not be quaternized or oxidized to the N-oxide. Inaddition, the nitrogen containing heterocyclic rings may or may not beN-protected.

The term “heterocyclealkyl” as used herein, refers to an heterocyclegroup as defined herein, appended to the parent molecular moiety throughan alkyl group as defined herein.

The term “hydroxy,” as used herein, refers to —OH.

The term “hydroxyalkyl” as used herein, refers to an alkyl groupsubstituted by at least one hydroxy group. Representative examples ofhydroxyalkyl include, but are not limited to 1-hydroxy-1-methylethyl and2-hydroxy-1,1-dimethylethyl.

The term “nitro,” as used herein, refers to —NO₂.

The term “nitroalkyl” as used herein, refers to an alkyl groupsubstituted by at least one nitro group.

The term “oxo,” as used herein, refers to ═O.

It is understood that each of the terms as defined hereinabove:alkanoyl, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,alkylamino, alkylaminocarbonyl, alkynyl, aryl, arylalkyl, cyanoalkyl,cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl,dialkylamino, dialkylaminocarbonyl, haloalkoxy, haloalkenyl, haloalkyl,heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl,hydroxyalkyl, nitroalkyl, may be unsubstituted or substituted.

The term “treating” as used herein, refers to reversing, alleviating,inhibiting the progress of, or preventing the disorder or condition, orone or more symptoms of such disorder or condition to which such termapplies. The term “treatment”, as used herein, refers to the act oftreating, as “treating” is defined immediately above.

A “patient” is any individual treated with a compound or combination ofcompounds of the present invention, or a therapeutically acceptablesalt, solyate, prodrug, or salt of a prodrug, as defined herein.Patients include humans, as well as other animals such as companionanimals (e.g. dogs and cats) and livestock. Patients may be experiencingone or more symptoms of a condition responsive to HIV modulation, or maybe free of such symptom(s) (i.e. treatment may be prophylactic).

In a first embodiment the present invention provides a compound offormula (I)

or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, wherein:

-   A is

-   X is O, S or NH;-   Y is O, S or NH;-   B is H or —CH₂R₉;-   L is —C(═O), —C(═S), —C(═NH) or —S(O)₂;-   RA is —N(H)C(O)R⁸, —O(a), —OC(O)OR_(a), —NR_(a)R_(b),    —N(R_(b))S(O)₂R_(a), —N(R_(b))alkylN(R_(b))S(O)₂R_(a),-   —N(R_(b))alkylN(R_(b))C(O)OR_(a),    —N(R_(b))alkylN(R_(b))C(O)NR_(a)R_(b), -alkylSR_(a), -alkylS(O)R_(a)    or -alkylS(O)₂R_(a);-   R¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,    heterocycle, aryl or heteroaryl; wherein each R¹ is substituted with    0, 1 or 2 substituents independently selected from the group    consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl,    hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),    —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂, and    R^(1a);-   R^(1a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(1a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R² is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,    heterocycle, aryl or heteroaryl; wherein each R² is substituted with    0, 1 or 2 substituents independently selected from the group    consisting of halo, —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a),    —NR_(a)R_(b), —NR_(b)C(O)R_(a), —N(R_(b))C(O)OR_(a),    —N(R_(a))C(═N)NR_(a)R_(b), —N(R_(a))C(O)NR_(a)R_(b),    —C(O)NR_(a)R_(b), —C(O)OR_(a) and R²a;-   R^(2a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(2a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(allyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R³ is alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, -alkylOR_(a),    -alkylSR_(a), -alkylSOR_(a), -alkylSO₂R_(a), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)OR_(a),    -alkylN(R_(a))C(═N)NR_(a)R_(b), -alkylN(R_(a))C(O)NR_(a)R_(b),    -alkylC(O)NR_(a)R_(b), -alkylC(O)OR_(a), cycloalkyl,    cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle,    heterocyclealkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;    wherein the cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl,    cycloalkyl moiety of the cycloalkylalkyl, cycloalkenyl moiety of the    cycloalkenylalkyl, heterocycle moiety of the heterocyclealkyl,    heteroaryl moiety of the heteroarylalkyl and the aryl moiety of the    arylalkyl are independently substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and    R^(3a);-   R^(3a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(3a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    oxo, alkyl, alkenyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), and -alkylC(O)N(alkyl)₂;-   R⁴ is H and R⁵ is OR¹⁶; or-   R⁵ is H and R⁴ is OR¹⁶; or-   R⁴ and R⁵ are —OR¹⁶;-   R⁶ is alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, -alkylOR_(a),    -alkylSR_(a), -alkylSOR_(a), -alkylSO₂R_(a), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)OR_(a),    -alkylN(R_(a))C(═N)NR_(a)R_(b), -alkylN(R_(a))C(O)NR_(a)R_(b),    -alkylC(O)NR_(a)R_(b), -alkylC(O)OR_(a), cycloalkyl,    cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle,    heterocyclealkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;    wherein the cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl,    cycloalkyl moiety of the cycloalkylalkyl, cycloalkenyl moiety of the    cycloalkenylalkyl, heterocycle moiety of the heterocyclealkyl,    heteroaryl moiety of the heteroarylalkyl and the aryl moiety of the    arylalkyl are independently substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and    R^(6a);-   R^(6a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(6a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    oxo, alkyl, alkenyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), and -alkylC(O)N(alkyl)₂;-   R⁷ is —N(R_(b))C(O)OR_(a), alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, heterocycle, aryl or heteroaryl; wherein the alkyl,    alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl and    heteroaryl are independently substituted with 0, 1 or 2 substituents    independently selected from the group consisting of halo, —OR_(a),    —OC(O)R_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —NR_(a)R_(b),    —N(R_(b))C(O)R_(a), —N(R_(b))C(O)OR_(a), —N(R_(a))C(═N)NR_(a)R_(b),    —N(R_(a))C(O)NR_(a)R_(b), —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(7a);-   R^(7a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(7a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R⁸ is —OR_(a), —NR_(a)R_(b), —N(R_(b))C(O)OR_(a), -alkylOR_(a),    -alkylOC(O)R_(a), or -alkylC(O)R_(a);-   R⁹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R⁹ is substituted with 0, 1,    2 or 3 substituents independently selected from the group consisting    of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro, oxo,    —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))SO₂R_(a),    —N(R_(b))SO₂NR_(a)R_(b), —N(R_(b))C(O)NR_(a)R_(b),    —N(R_(b))C(O)OR_(a), —C(O)R_(a), —C(O)NR_(a)R_(b), —C(O)OR_(a),    haloalkyl, nitroalkyl, cynaoalkyl, formylalkyl, -alkylOR_(a),    -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)OR_(a), -alkylN(R_(b))SO₂NR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkylC(O)R_(a),    -alkylC(O)NR_(a)R_(b) and R^(9a);-   R^(9a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(9a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹⁰ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R¹⁰ is substituted with 0,    1, 2 or 3 substituents independently selected from the group    consisting of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro,    oxo, —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), —SO₂)R_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))SO₂R_(a),    —N(R_(b))SO₂NR_(a)R_(b), —N(R_(b))C(O)NR_(a)R_(b),    —N(R_(b))C(O)OR_(a), —C(O)R_(a), —C(O)NR_(a)R_(b), —C(O)OR_(a),    haloalkyl, nitroalkyl, cynaoalkyl, formylalkyl, -alkylOR_(a),    -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)OR_(a), -alkylN(R_(b))SO₂NR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkylC(O)R_(a),    -alkylC(O)NR_(a)R_(b) and R^(10a);-   R^(10a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or    heteroaryl; wherein each R^(10a) is substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R¹¹ is substituted with 0,    1, 2 or 3 substituents independently selected from the group    consisting of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro,    oxo, —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))SO₂R_(a),    —N(R_(b))SO₂NR_(a)R_(b), —N(R_(b))C(O)NR_(a)R_(b),    —N(R_(b))C(O)OR_(a), —C(O)R_(a), —C(O)NR_(a)R_(b), —C(O)OR_(a),    haloalkyl, nitroalkyl, cynaoalkyl, formylalkyl, -alkylOR_(a),    -alkyl-O—P(O)(OR_(a))(OR_(b)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)OR_(a), -alkylN(R_(b))SO₂NR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkylC(O)R_(a),    -alkylC(O)NR_(a)R_(b) and R^(11a);-   R^(11a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or    heteroaryl; wherein each R¹¹ is substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R¹² is alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl or    cycloalkenylalkyl; wherein each R¹² is substituted with 0, 1 or 2    substituents independently selected from the group consisting of    hydroxy, alkoxy and halo;-   R¹³ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R¹³ is substituted with 0,    1, 2 or 3 substituents independently selected from the group    consisting of alkyl, alkenyl, alkynyl, cyano, halo, nitro, oxo,    —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))C(O)OR_(a),    —C(O)NR_(a)R_(b), —C(O)OR_(a), haloalkyl, nitroalkyl, cynaoalkyl,    -alkylOR_(a), -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkyl-C(O)NR_(a)R_(b) and    R^(13a);-   R^(13a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or    heteroaryl; wherein each R^(13a) is substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹⁴ is —OR_(a), -alkylOR_(a), aryl, heteroaryl or heterocycle;    wherein the aryl, heteroaryl and heterocycle are independently    substituted with 0, 1, 2, 3 or 4 substituents independently selected    from the group consisting of cyano, halo, nitro, oxo, alkyl,    alkenyl, alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂,    —SH, —S(alkyl), —SO₂(alkyl), —S(O)₂NR_(a)R_(b), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)2, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹⁶ is hydrogen or R¹⁵;-   R¹⁵ is

-   R₁₀₃ is C(R₁₀₅)₂, O or —N(R₁₀₅);-   R₁₀₄ is hydrogen, alkyl, haloalkyl, alkoxycarbonyl, aminocarbonyl,    alkylaminocarbonyl or dialkylaminocarbonyl,-   each M is independently selected from the group consisting of H,    —N(R₁₀₅)₂, alkyl, alkenyl, and-   R₁₀₆; wherein 1 to 4 —CH₂ radicals of the alkyl or alkenyl, other    than the —CH₂ radical that is bound to Z, is optionally replaced by    a heteroatom group selected from the group consisting of O, S, S(O),    SO₂ and N(R₁₀₅); and wherein any hydrogen in said alkyl, alkenyl or    R₁₀₆ is optionally replaced with a substituent selected from the    group consisting of oxo, —OR₁₀₅, —R₁₀₅, —N(R₁₀₅)₂, —CN, —C(O)OR₁₀₅,    —C(O)N(R₁₀₅)₂, —SO₂N(R₁₀₅), —N(R₁₀₅)C(O)R₁₀₅, —C(O)R —S(O)R₁₀₅,    —SO₂R₁₀₅, —OCF₃, —SR₁₀₆, —SOR₁₀₆, —SO₂R₁₀₆, —N(R₁₀₅)SO₂R₁₀₅, halo,    —CF₃, NO₂ and phenyl; provided that when M is —N(R₁₀₅)₂, Z₁ and Z₂    are —CH₂;-   Z₁ is CH₂, O, S, —N(R₁₀₅), or, when M is absent, H;-   Z₂ is CH₂, O, S or —N(R₁₀₅);-   Q is O or S;-   W is P or S; wherein when W is S, Z₁ and Z₂ are not S;-   M′ is H, alkyl, alkenyl or R₁₀₆; wherein 1 to 4 —CH₂ radicals of the    alkyl or alkenyl is optionally replaced by a heteroatom group    selected from O, S, S(O), SO₂, or N(R₁₀₅); and wherein any, hydrogen    in said alkyl, alkenyl or R₁₀₆ is optionally replaced with a    substituent selected from the group consisting of oxo, —OR₁₀₅,    —R₁₀₆, —N(R₁₀₅)₂, —CN, —C(O)OR₁₀₅, —C(O)N(R₁₀₅)₂, —SO₂N(R₁₀₅),    —N(R₁₀₅)C(O)R₁₀₅, —C(O)R₁₀₅, —SR₁₀₅, —S(O)R₁₀₅, —SO₂R₁₀₅, —OCF₃,    —SR₁₀₆, —SOR₁₀₆, —SO₂R₁₀₆, —N(R₁₀₅)SO₂R₁₀₅, halo, —CF₃ and NO₂;-   R₁₀₆ is a monocyclic or bicyclic ring system selected from the group    consisting of aryl, cycloalkyl, cycloalkenyl heteroaryl and    heterocycle; wherein any of said heteroaryl and heterocycle ring    systems contains one or more heteroatoms selected from the group    consisting of O, N, S, SO, SO₂ and N(R₁₀₅); and wherein any of said    ring system is substituted with 0, 1, 2, 3, 4, 5 or 6 substituents    selected from the group consisting of hydroxy, alkyl, alkoxy, and    —OC(O)alkyl;-   each R₁₀₅ is independently selected from the group consisting of H    or alkyl; wherein said alkyl is optionally substituted with a ring    system selected from the group consisting of aryl, cycloalkyl,    cycloalkenyl, heteroaryl and heterocycle; wherein any of said    heteroaryl and heterocycle ring systems contains one or more    heteroatoms selected from the group consisting of O, N, S, SO, SO₂,    and N(R₁₀₅); and wherein any one of said ring systems is substituted    with 0, 1, 2, 3 or 4 substituents selected from the group consisting    of oxo, —OR₁₀₅, —R₁₀₅, —N(R₁₀₅)₂, —N(R₁₀₅)C(O)R₁₀₅, —CN, —C(O)OR₁₀₅,    —C(O)N(R₁₀₅)₂, halo and —CF₃;-   each R₁₀₇ and R₁₀₈ are independently selected from the group    consisting of hydrogen and alkyl;-   q is 0 or 1;-   m is 0 or 1;-   m′ is 0 or 1;-   m″ is 0 or 1;-   r is 0, 1, 2, 3 or 4;-   t is 0 or 1;-   R_(a) and R_(b) at each occurrence are independently selected from    the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    cycloalkyl, aryl, heteroaryl and heterocycle; wherein each R_(a) and    R_(b), at each occurrence, is independently substituted with 0, 1, 2    or 3 substituents independently selected from the group consisting    of cyano, nitro, halo, oxo, alkyl, alkenyl, alkynyl, hydroxy,    alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and R_(a);-   alternatively, R_(a) and R_(b), together with the nitrogen atom to    which they are attached, form a ring selected from the group    consisting of heteroaryl and heterocycle; wherein each of the    heteroaryl and heterocycle is independently substituted with 0, 1, 2    or 3 substituents independently selected from the group consisting    of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo,    hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl₂, —SH, —S(alkyl),    —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, formylalkyl,    nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH₂,    -alkylN(H)(alkyl), -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂,    -alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH,    -alkylC(O)Oalkyl, -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl),    -alkylC(O)N(alkyl)₂ and R_(a);-   R_(a) is aryl, heteroaryl or heterocycle; wherein each R_(a) is    independently substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of halo, nitro,    oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkyl-NH₂, -alkyl-N(H)(alkyl), -alkyl-N(alkyl)₂,    -alkyl-N(H)C(O)NH₂, -alkyl-N(H)C(O)N(H)(alkyl),    -alkyl-N(H)C(O)N(alkyl)₂, -alkyl-C(O)OH, -alkyl-C(O)Oalkyl,    -alkyl-C(O)NH₂, -alkyl-C(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂; and-   n is 1 or 2.

For example, the present invention of the first embodiment provides acompound of formula (I) wherein W is P; Q is O; Z₁ and Z₂ are O; and X,Y, B, L, R^(A), R¹, R^(1a), R², R^(2a), R³, R^(3a), R⁴, R⁵, R⁶, R^(6a),R⁷, R^(7a), R⁸, R⁹, R^(9a), R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R¹³,R^(13a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, M′, R₁₀₆, R₁₀₇, R₁₀₈q, m,m′, m″, r, t, R_(a), R_(b), R_(c), and n are as defined in formula (I).

For example, the present invention of the first embodiment provides acompound of formula (I) wherein R⁴ is H; R⁵ is OR¹⁶ and X, Y, B, L,R^(A), R¹, R^(1a), R², R^(2a), R³, R^(3a), R⁶, R^(6a), R⁷, R^(7a), R⁸,R⁹, R^(9a), R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R¹³, R^(13a), R¹⁴, R¹⁵,R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈q, m, m′,m″, r, t, R_(a), R_(b), R_(c), and n are as defined in formula (I).

For example, the present invention provides a compound of formula (I)wherein R⁴is OR¹⁶, R⁵ is H; and X, Y, B, L, R^(A), R¹, R^(1a), R², R³,R^(3a), R⁶, R^(6a), R⁷, R^(7a), R⁸, R⁹, R^(9a), R¹⁰, R^(10a), R¹¹,R^(11a), R¹², R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂,Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈q, m, m′, m″, r, t, R_(a), R_(b), R_(c), and nare as defined in formula (I).

For example, the present invention provides a compound of formula (I)wherein L is —C(═O) or —C(═S); X is O; Y is O; and B, R^(A), R¹, R^(1a),R², R^(2a), R³, R^(3a), R⁴, R⁵, R⁶, R^(6a), R⁷, R^(7a), R⁸, R⁹, R^(9a),R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃,R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈q, m, m′, m″, r, t,R_(a), R_(b), R_(c), and n are as defined in formula (I).

For example, the present invention provides a compound of formula (I)wherein L is —C(═O) or —C(═S); X is O; Y is O; R⁴is H; R⁵ is OR¹⁶; andB, R^(A), R¹, R^(1a), R², R^(2a), R³, R^(3a), R⁶, R^(6a), R⁷, R^(7a),R⁸, R⁹, R^(9a), R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R¹³, R^(13a), R¹⁴, R¹⁵,R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈q, m, m′,m″, r, t R_(a), R_(b), R_(c), and n are as defined in formula (I).

For example, the present invention provides a compound of formula (I)wherein L is —C(═O) or —C(═S); X is O; Y is O; R⁴ is OR¹; R⁵ is H; andB, R^(A), R¹, R^(1a), R², R^(2a), R³, R^(3a), R⁶, R^(6a), R⁷, R^(7a),R⁸, R⁹, R^(9a), R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R¹³, R^(13a), R¹⁴ ,R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈q, m,m′, m″, r, t , R_(a), R_(b), R_(c), and n are as defined in formula (I).

For example, the present invention provides a compound of formula (I)wherein L is —C(═O) or —C(═S); X is O; Y is O; R⁴ is H, R⁵ is OR¹⁶; R²is alkyl; and B, R^(A), R¹, R^(1a), R³, R³a, R⁶, R^(6a), R⁷, R^(7a), R⁸,R⁹, R^(9a), R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R¹³, R^(13a), R¹⁴, R¹⁵,R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈q, m, m′,m″, r, t, R_(a), R_(b), R_(c), and n are as defined in formula (I).

For example, the present invention provides a compound of formula (I)wherein L is —C(═O) or —C(═S); X is O; Y is O; R⁴ is OR¹⁶, R⁵ is H; R²is alkyl; and B, R^(A), R¹, R^(1a), R³, R^(3a), R⁶, R^(6a), R⁷, R^(7a),R⁸, R⁹, R^(9a), R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R¹³, R^(13a), R¹⁴, R¹⁵,R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈q, m, m′,m″, r, t, R_(a), R_(b), R_(c), and n are as defined in formula (I).

For example, the present invention provides a compound of formula (I)wherein L is —C(═O) or C(═S); X is O; Y is O; R⁴ is H; R⁵ is OR¹⁶; R² isalkyl; R³ is arylalkyl wherein the aryl moiety of the arylalkyl issubstituted with 0, 1, 2, 3 or 4 substituents independently selectedfrom the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl,alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH,—S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl,—N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH,—C(O)Oalkyl, —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl,hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),-alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),-alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl, -alkylC(O)NH₂,-alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and R^(3a); and B, R^(A), R¹,R^(1a), R^(3a), R⁶, R^(6a), R⁷, R^(7a), R⁸, R⁹, R^(9a), R¹⁰, R^(10a),R¹¹, R^(11a), R¹², R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁,Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈q, m, m′, m″, r, t, R_(a), R_(b), R_(c),and n are as defined in formula (I).

For example, the present invention provides a compound of formula (I)wherein L is —C(═O) or —C(═S); X is O; Y is O; R⁴ is OR¹⁶; R⁵ is H; R²is alkyl; R³ is arylalkyl wherein the aryl moiety of the arylalkyl issubstituted with 0, 1, 2, 3 or 4 substituents independently selectedfrom the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl,alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH,—S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl,—N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH,—C(O)Oalkyl, —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl,hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),-alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),-alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl, -alkylC(O)NH₂,-alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and R^(3a); and B, R^(A), R¹,R^(1a), R^(3a), R⁶, R^(6a), R⁷, R^(7a), R⁸, R⁹, R^(9a), R¹⁰, R^(10a),R¹¹, R^(11a), R¹², R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁,Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈ q, m, m′, m″, r, t, R_(a), R_(b), R_(c),and n are as defined in formula (I).

For example, the present invention provides a compound of formula (I)wherein L is —C(═O) or —C(═S); X is O; Y is O; R⁴ is H; R⁵ is OR¹⁶; R²is alkyl; R³ is arylalkyl wherein the aryl moiety of the arylalkyl isunsubstituted or substituted with one R^(3a); and B, R^(A), R¹, R^(1a),R^(3a), R⁶, R^(6a), R⁷, R^(7a), R⁸, R⁹, R^(9a), R¹⁰, R^(10a), R¹¹,R^(11a), R¹², R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂,Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈ , m, m′, m″, r, t, R_(a), R_(b), R_(c), n andthe substituents of R^(3a) are as defined in formula (I).

For example, the present invention provides a compound of formula (I)wherein L is —C(═O) or —C(═S); X is O; Y is O; R⁴ is OR¹⁶; R⁵is H; R² isalkyl; R³ is arylalkyl wherein the aryl moiety of the arylalkyl isunsubstituted or substituted with one R^(3a); and B, R^(A), R¹, R^(1a),R^(3a), R⁶, R^(6a), R⁷, R^(7a), R⁸, R⁹, R^(9a), R¹⁰, R^(10a), R¹¹,R^(11a), R¹², R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂,Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈ q, m, m′, m″, r, t, R_(a), R_(b), R_(c), nand the substituents of R^(3a) are as defined in formula (I).

For example, the present invention provides a compound of formula (I)wherein L is —C(═) or —C(═S); X is O; Y is O; R⁴ is H; R⁵ is OR¹⁶; R² isalkyl; R³ is arylalkyl wherein the aryl moiety of the arylalkyl isunsubstituted or substituted with one R^(3a); R⁶ is arylalkylsubstituted with 0 or one R^(6a); and B, R^(A), R¹, R^(1a), R^(3a),R^(6a), R⁷, R^(7a), R⁸, R⁹, R^(9a), R¹⁰, R^(10a), R¹¹, R^(11a), R¹²,R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶ R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₇,R₁₀₈, q, m, m′, m″m , r, t, R_(a), R_(b), R_(c), n and the substituentsof R^(3a) and R^(6a) are as defined in formula (I).

For example, the present invention provides a compound of formula (I)wherein L is —C(═) or —C(═S); X is O; Y is O; R⁴ is OR¹⁶; R⁵is H; R² isalkyl; R³ is arylalkyl wherein the aryl moiety of the arylalkyl isunsubstituted or substituted with one R^(3a); R⁶ is arylalkylsubstituted with 0 or one R^(6a); and B, R^(A), R¹, R^(1a), R^(3a),R^(6a), R⁷, R^(7a), R⁸, R⁹, R^(9a), R¹⁰, R^(10a), R¹¹, R^(11a), R¹²,R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶ R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆,R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c), n and thesubstituents of R^(3a) and R^(6a) are as defined in formula (I).

For example, the present invention provides a compound of formula (I)wherein L is —C(═O) or —C(═S); X is O; Y is O; R⁴ is H; R⁵ is OR¹⁶; R²is alkyl; R³ is arylalkyl wherein the aryl moiety of the arylalkyl isunsubstituted or substituted with one R^(3a); R⁶ is arylalkylsubstituted with 0 or one R^(6a); R₁₀₄ is hydrogen or alkyl, each M ishydrogen or alkyl, Z₁ is O, Z₂ is O, Q is O, W is P, M′ is hydrogen oralkyl, and B, R^(A), R¹, R^(1a), R^(3a), R^(6a), R⁷, R^(7a), R⁸, R⁹,R^(9a), R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶,R₁₀₃, R₁₀₅, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c), nand substituents of R^(3a), M, M′ and R^(6a) are as defined in formula(I).

For example, the present invention provides a compound of formula (I)wherein L is —C(═O) or —C(═S); X is O; Y is O; R⁴ is OR¹⁶; R⁵is H; R² isalkyl; R³ is arylalkyl wherein the aryl moiety of the arylalkyl isunsubstituted or substituted with one R^(3a); R⁶ is arylalkylsubstituted with 0 or one R^(6a); R₁₀₄ is hydrogen or alkyl, R₁₀₅ ishydrogen or alkyl, each M is hydrogen or alkyl, Z₁ is O, Z₂ is O, Q isO, W is P, M′ is hydrogen or alkyl, and B, R^(A), R¹, R^(1a), R^(3a),R^(6a), R⁷, R^(7a), R⁸, R⁹, R^(9a), R¹⁰, R^(10a), R¹¹, R^(11a), R¹²,R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t,R_(a), R_(b), R_(c), n and the substituents of R^(3a), M, M′ and R^(6a)are as defined in formula (I).

For example, the present invention provides a compound of formula (I)wherein L is —C(═) or —C(═S); X is O; Y is O; R⁴ is H; R⁵ is OR¹⁶; R² isalkyl; R³ is arylalkyl wherein the aryl moiety of the arylalkyl isunsubstituted or substituted with one R^(3a); R^(3a) is aryl orheteroaryl; wherein each R^(3a) is unsubstituted or substituted, and B,R^(A), R¹, R^(1a), R⁶, R^(6a), R⁷, R^(7a), R⁸, R⁹, R^(9a), R¹⁰, R^(10a),R¹¹, R^(11a), R¹², R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁,Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c),n and the substituents of R³a are as defined in formula (I).

For example, the present invention provides a compound of formula (I)wherein L is —C(═O) or —C(═S); X is O; Y is O; R⁴ is OR¹⁶; R⁵ is H; R²is alkyl; R³ is arylalkyl wherein the aryl moiety of the arylalkyl isunsubstituted or substituted with one R^(3a); R^(3a) is aryl orheteroaryl;

wherein each R^(3a) is wherein each R^(3a) is unsubstituted orsubstituted; and B, R^(A), R¹, R^(1a), R⁶, R^(6a), R⁷, R^(7a), R⁸, R⁹,R^(9a), R¹⁰, R_(10a), R¹¹, R^(11a), R¹², R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶,R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″,r, t, R_(a), R_(b), R_(c), n and the substituents of R^(3a) are asdefined in formula (I).

For example, the present invention provides a compound of formula (I)wherein L is —C(═O) or —C(═S); X is O; Y is O; R⁴ is H; R⁵ is OR¹⁶; R²is C1, C2, C3, C4 or C5, alkyl, R³ is phenylmethyl wherein the phenylmoiety of phenylmethyl is unsubstituted or substituted with one R^(3a),R^(3a) is aryl or heteroaryl wherein each R^(3a) is unsubstituted orsubstituted; and B, R^(A), R¹, R^(1a), R⁶, R^(6a), R⁷, R^(7a), R⁸, R⁹,R^(9a), R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶,R₁₀₃, R₁₀₄, R₁₀₅ M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r,t, R_(a), R_(b), R_(c), n and the substituents of R^(3a) are as definedin formula (I).

For example, the present invention provides a compound of formula (I)wherein L is —C(═O) or —C(═S); X is O; Y is O; R⁴ is OR¹⁶; R⁵ is H; R²is C1, C2, C3, C4 or C5 alkyl, R³ is phenylmethyl wherein the phenylmoiety of phenylmethyl is unsubstituted or substituted with one R^(3a),R^(3a) is aryl or heteroaryl; wherein each R^(3a) is unsubstituted orsubstituted; and B, R^(A), R¹, R^(1a), R⁶, R^(6a), R⁷, R^(7a), R⁸, R⁹,R^(9a), R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R¹³, R^(13a), R¹⁴, R¹⁵, R⁶,R₁₀₃, R₁₀₄, R₁₀₅ M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r,t, R_(a), R_(b), R_(c), n and the substituents of R^(3a) are as definedin formula (I).

For example, the present invention provides a compound of formula (I)wherein L is —C(═O) or —C(═S); X is O; Y is O; R⁴ is H; R⁵ is OR¹⁶; R²is C1, C2, C3, C4 or C5 alkyl, R³ is phenylmethyl wherein the phenylmoiety of the phenylmethyl is unsubstituted or substituted with oneR^(3a), R^(3a) is unsubstituted or substituted pyridyl and B, R^(A), R¹,R^(1a), R⁶, R^(6a), R⁷, R^(7a), R⁸, R⁹, R^(9a), R¹⁰, R^(10a), R¹¹,R^(11a), R¹², R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂,Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c), nand the substituents of R^(3a) are as defined in formula (I).

For example, the present invention provides a compound of formula (I)wherein L is —C(═) or —C(═S); X is O; Y is O; R⁴ is OR¹⁶; R⁵is H; R² isC1, C2, C3, C4 or C5 alkyl, R³ is phenylmethyl wherein the phenyl moietyof the phenylmethyl is unsubstituted or substituted with one R^(3a),R^(3a) is unsubstituted or substituted pyridyl; and B, R^(A), R¹,R^(1a), R⁶, R^(6a), R⁷, R^(7a), R⁸, R⁹, R^(9a), R¹⁰, R^(10a), R¹¹,R^(11a), R¹², R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂,Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c), nand the substituents of R^(3a) are as defined in formula (I).

For example, the present invention provides a compound of formula (I)wherein L is —C(═O) or —C(═S); X is O; Y is O; R⁴is H; R⁵ is OR¹⁶; R² isC1, C2, C3, C4 or C5 alkyl, R³ is phenylmethyl wherein the phenyl moietyof the phenylmethyl is unsubstituted or substituted with one R^(3a)wherein R^(3a) is unsubstituted or substituted pyridyl; R⁶ isphenylmethyl substituted with 0 or one R^(6a) wherein R^(6a) isunsubstituted or substituted aryl or unsubstituted or substitutedheteroaryl; and B, R^(A), R¹, R^(1a), R⁷, R^(7a), R⁸, R⁹, R^(9a), R¹⁰,R^(10a), R¹¹, R^(11a), R¹², R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃ , R₁₀₄,R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a),R_(b), R_(c), n and the substituents of R^(3a) and R^(6a) are as definedin formula (I).

For example, the present invention provides a compound of formula (I)wherein L is —C(═O) or —C(═S); X is O; Y is O; R⁴ is OR¹⁶; R⁵is H; R² isC1, C2, C3, C4 or C5 alkyl, R³ is phenylmethyl wherein the phenyl moietyof the phenylmethyl is unsubstituted or substituted with one R^(3a),R^(3a) is unsubstituted or substituted pyridyl; R⁶ is phenylmethylsubstituted with 0 or one R^(6a) wherein R^(6a) is unsubstituted orsubstituted aryl or unsubstituted or substituted heteroaryl; and B,R^(A), R¹, R^(1a), R⁷, R^(7a), R⁸, R⁹, R^(9a), R¹⁰, R^(10a), R¹¹,R^(11a), R¹², R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R^(3a) and R⁶ areas defined in formula (I).

For example, the present invention provides a compound of formula (I)wherein L is —C(═O) or —C(═S); X is O; Y is O; R⁴ is H; R⁵ is OR¹⁶; R²is C1, C2, C3, C4 or C5 alkyl, R³ is phenylmethyl wherein the phenylmoiety of the phenylmethyl is unsubstituted or substituted with oneR^(3a) wherein R^(3a) is unsubstituted or substituted pyridyl; R⁶ isphenylmethyl substituted with 0 or one R^(6a) wherein R^(6a) isunsubstituted or substituted pyridyl; and B, R^(A), R¹, R^(1a), R⁷,R^(7a), R⁸, R⁹, R^(9a), R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R¹³, R^(13a),R¹⁴, R¹⁵, R¹⁶, R_(R) ₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c),n and the substituents of R^(3a) and R^(6a) are as defined in formula(I).

For example, the present invention provides a compound of formula (I)wherein L is —C(═O) or —C(═S); X is O; Y is O; R⁴ is OR¹⁶; R⁵is H; R² isC1, C2, C3, C4 or C5 alkyl, R³ is phenylmethyl wherein the phenyl moietyof the phenylmethyl is unsubstituted or substituted with one R^(3a) ,R^(3a) is unsubstituted or substituted pyridyl; R⁶ is phenylmethylsubstituted with 0 or one R^(6a) wherein R^(6a) is unsubstituted orsubstituted pyridyl; and B, R^(A), R¹, R^(1a), R⁷, R^(7a), R⁸, R⁹,R^(9a) , R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶,R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″,r, t, R_(a), R_(b), R_(c), n and the substituents of R^(3a) and R⁶ areas defined in formula (I).

For example, the present invention provides a compound of formula (I)wherein L is —C(═O) or —C(═S); X is O; Y is O; R⁴ is H; R⁵ is OR¹⁶; R²is 1-methylpropyl, tert-butyl or isopropyl, R³ is phenylmethyl whereinthe phenyl moiety of the phenylmethyl is unsubstituted or substitutedwith one R^(3a), R^(3a) is unsubstituted or substituted pyridyl; R⁶ isphenylmethyl substituted with 0 or one R^(6a), wherein R^(6a) isunsubstituted or substituted pyridyl; and B, R^(A), R¹, R^(1a), R⁷,R^(7a), R⁸, R⁹, R^(9a), R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R¹³, R^(13a),R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈,q, m, m′, m″, r, t, R_(a), R_(b), R_(c), n and the substituents ofR^(3a) and R^(6a) are as defined in formula (I).

For example, the present invention provides a compound of formula (I)wherein L is —C(═O) or —C(═S); X is O; Y is O; R⁴ is OR¹⁶; R⁵is H; R² is1-methylpropyl, tert-butyl or isopropyl, R³ is phenylmethyl wherein thephenyl moiety of the phenylmethyl is unsubstituted or substituted withone R^(3a) wherein R^(3a) is unsubstituted or substituted pyridyl; R⁶ isphenylmethyl substituted with 0 or one R^(6a), wherein R^(6a) isunsubstituted or substituted pyridyl; and B, R^(A), R¹, R^(1a), R⁷,R^(7a), R⁸, R⁹, R^(9a), R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R¹³, R^(13a),R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈,q, m, m′, m″, r, t, R_(a), R_(b), R_(c), n and the substituents ofR^(3a) and R^(6a) are as defined in formula (I).

For example, the present invention provides a compound of formula (I)wherein L is —C(═O) or —C(═S); X is O; Y is O; R⁴ is H; R⁵ is OR¹⁶; R²is 1-methylpropyl, tert-butyl or isopropyl, R³ is phenylmethyl whereinthe phenyl moiety of the phenylmethyl is unsubstituted or substitutedwith one R^(3a), R^(3a) is unsubstituted or substituted pyridyl; R⁶ isphenylmethyl substituted with 0 or one R^(6a), wherein R^(6a) isunsubstituted or substituted pyridyl; W is P; Q is O; Z₁ and Z₂ are O;and B, R^(A , R) ^(1a), R⁷, R^(7a), R⁸, R⁹, R^(9a), R¹⁰, R^(10a), R¹¹,R^(11a), R¹², R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, M′,R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c), n and thesubstituents of R^(3a) and R^(6a) are as defined in formula (I).

For example, the present invention provides a compound of formula (I)wherein L is —C(═O) or —C(═S); X is O; Y is O; R⁴ is OR¹⁶; R⁵is H; R² is1-methylpropyl, tert-butyl or isopropyl, R³ is phenylmethyl wherein thephenyl moiety of the phenylmethyl is unsubstituted or substituted withone R^(3a) wherein R^(3a) is unsubstituted or substituted pyridyl; R⁶ isphenylmethyl substituted with 0 or one R^(6a), wherein R^(6a) isunsubstituted or substituted pyridyl; W is P; Q is O; Z₁ and Z₂ are O;and B, R^(A), R¹, R^(1a), R⁷, R^(7a), R⁸, R⁹, R^(9a), R¹⁰, R^(10a), R¹¹,R^(11a), R¹², R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, M′,R₁₀₆, R₁₀₇, R₁₀₈, m, m′, m″, r, t, R_(a), R_(b), R_(c), n and thesubstituents of R^(3a) and R^(6a) are as defined in formula (I).

Exemplary compounds of the present invention of formula (I) include, butnot limited to, the following:

methyl7-benzyl-1,10-ditert-butyl-6-hydroxy-2,9,12-trioxo-4-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl4-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl1-{[(1-benzyl-3-hydroxy-4-{[3-methyl-2-(2-oxo-3-{[2-(2-pyrindinyl)-1,3-thiazol-4-yl]methyl}-1-imidazolidinyl)pentanoyl])amino}-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamate;

methyl1-({[1-benzyl-3-hydroxy-4-({3-methyl-2-[2-oxo-3-(4-quinolinylmethyl)-1-imidazolidinyl]pentanoyl}amino)-5-phenylpentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl1-({[1-benzyl-3-hydroxy-4-({3-methyl-2-[2-oxo-3-(4-quinolinylmethyl)-1-imidazolidinyl]pentanoyl}amino)-5-phenylpentyl]amino}carbonyl)-2-methylbutylcarbamate;

methyl1-{[(1-benzyl-3-hydroxy-4-{[2-(3-{[2-(methoxymethyl)-1,3-thiazol-4-yl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamate;

methyl1-[({1-benzyl-3-hydroxy-4-[(3-methyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({1-benzyl-2-hydroxy-4-[(3-methyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({1-benzyl-2-hydroxy-4-[(3-methyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenylpentyl}amino)carbonyl]-2-methylbutylcarbamate;

methyl1-[({1-benzyl-4-[(3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({1-benzyl-2-hydroxy-4-[(3-methyl-2-{3-[(2-methyl-1,3-thiazol-5-yl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-{[(1-benzyl-2-hydroxy-4-{[3-methyl-2-(2-oxo-3-{[2-(3-pyridinyl)-1,3-thiazol-4-yl]methyl}-1-imidazolidinyl)pentanoyl]amino}-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamate;

methyl1-[({1-benzyl-2-hydroxy-4-[(3-methyl-2-{3-[(6-methyl-3-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({1-benzyl-4-[(3,3-dimethyl-2-{3-[(2-methyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({1-benzyl-2-hydroxy-4-[(3-methyl-2-{3-[(2-methyl-3-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-[(3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-{[(1-benzyl-2-hydroxy-4-{[2-(3-{[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamate;

methyl1-[({3-hydroxy-4-[(3-methyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-{[(1-benzyl-4-{[3,3-dimethyl-2-(2-oxo-3-{[2-(3-pyridinyl)-1,3-thiazol-4-yl]methyl}-1-imidazolidinyl)butanoyl]amino}-2-hydroxy-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamate;

methyl1-({[1-benzyl-4-({3,3-dimethyl-2-[2-oxo-3-(3-pyridinylmethyl)-1-imidazolidinyl]butanoyl}amino)-2-hydroxy-5-phenylpentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl1-[({3-hydroxy-4-[(3-methyl-2-{3-[(2-methyl-3-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({1-benzyl-4-[(3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-[(3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({1-benzyl-4-[(3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-[4-(2-pyridinyl)phenyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl 7-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-4-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl1-benzyl-3-hydroxy-4-({2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-5-[4-(2-pyridinyl)phenyl]pentylcarbamate;

(3R,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-yl1-benzyl-3-hydroxy-4-({2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-5-[4-(2-pyridinyl)phenyl]pentylcarbamate;

(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl1-benzyl-2-hydroxy-4-({2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-5-[4-(2-pyridinyl)phenyl]pentylcarbamate;

(3R,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-yl1-benzyl-2-hydroxy-4-({2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-5-[4-(2-pyridinyl)phenyl]pentylcarbamate;

methyl1-[({2-hydroxy-4-[(3-methyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-[(3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl 4-benzyl-10-tert-butyl-5-hydroxy-1-[1-methyl-i-(methylsulfanyl)ethyl]-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl 4-benzyl-10-tert-butyl-5-hydroxy-1-[1-methyl-i-(methylsulfonyl)ethyl]-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl 4-benzyl-10-tert-butyl-6-hydroxy-1-[1-methyl-i-(methylsulfanyl)ethyl]-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl 4-benzyl-10-tert-butyl-6-hydroxy-1-[1-methyl-i-(methylsulfonyl)ethyl]-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl1-[({4-{[(2S)-3,3-dimethyl-2-(2-oxo-3-{[2-(3-pyridinyl)-1,3-thiazol-4-yl]methyl}-1-imidazolidinyl)butanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-{[3,3-dimethyl-2-(2-oxo-3-{[2-(3-pyridinyl)-1,3-thiazol-4-yl]methyl}-1-imidazolidinyl)butanoyl]amino}-2-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({3-hydroxy-4-[(3-methyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2,4-dioxo-1-imidazolidinyl}pentanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({2-hydroxy-4-[(3-methyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2,4-dioxo-1-imidazolidinyl}pentanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-{[(2,6-dimethylphenoxy)acetyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-{[(2,6-dimethylphenoxy)acetyl]amino}-2-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({3-hydroxy-4-({(2S)-2-[3-(imidazo[1,5-a]pyridin-3-ylmethyl)-2-oxo-1-imidazolidinyl]-3,3-dimethylbutanoyl}amino)-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({2-hydroxy-4-({2-[3-(imidazo[1,5-a]pyridin-3-ylmethyl)-2-oxo-1-imidazolidinyl]-3,3-dimethylbutanoyl}amino)-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-({3,3-dimethyl-2-[2-oxo-3-(4-quinolinylmethyl)-1-imidazolidinyl]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-({(2S)-3,3-dimethyl-2-[2-oxo-3-(4-quinolinylmethyl)-1-imidazolidinyl]butanoyl}amino)-2-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({2-hydroxy-4-{[2-(3-{[6-(1-hydroxy-1-methylethyl)-2-pyrindinyl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({3-hydroxy-4-{[2-(3-{[6-(1-hydroxy-1-methylethyl)-2-pyrindinyl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-[(3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2,4-dioxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl1-benzyl-2-hydroxy-4-({2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-5-[4-(2-pyridinyl)phenyl]pentylcarbamate;

(3R,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-yl1-benzyl-2-hydroxy-4-({2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-5-[4-(2-pyridinyl)phenyl]pentylcarbamate;

methyl1-[({4-{[3,3-dimethyl-2-(2-oxo-3-{[2-(3-pyridinyl)-1,3-thiazol-4-yl]methyl}-1-imidazolidinyl)butanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-{[(2,6-dimethylphenoxy)acetyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({3-hydroxy-4-{[2-(3-{[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-[(3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2,4-dioxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-[(3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2,4-dioxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-({3,3-dimethyl-2-[2-oxo-3-(4-quinolinylmethyl)-1-imidazolidinyl]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-({3,3-dimethyl-2-[(phenoxyacetyl)amino]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl7-benzyl-1,10-ditert-butyl-6-hydroxy-2,9,12-trioxo-4-[4-(2-pyridinyl)benzyl]-14-oxa-3,8,11-triazapentadec-1-ylcarbamate;

methyl1-[({3-hydroxy-4-[(2-{3-[(2-isopropyl-1,3-thiazol-4-yl)methyl]-2,4-dioxo-1-imidazolidinyl}-3-methylpentanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-{[2-(2,4-dioxo-3-{[2-(3-pyridinyl)-1,3-thiazol-4-yl]methyl}-1-imidazolidinyl)-3-methylpentanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-{[3,3-dimethyl-2-({[(6-methyl-3-pyridinyl)oxy]acetyl}amino)butanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-[(3,3-dimethyl-2-{3-[(1-methyl-1H-benzimidazol-2-yl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-[(3,3-dimethyl-2-{3-[(2-methyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

3-pyridinylmethyl4-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

benzyl4-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl7-benzyl-1,10-ditert-butyl-6-hydroxy-13-methyl-2,9,12-trioxo-14-phenyl-4-[4-(2-pyridinyl)benzyl]-3,8,11,13-tetraazatetradec-1-ylcarbamate;

methyl7-benzyl-1,10-ditert-butyl-6-hydroxy-13-methyl-2,9,12-trioxo-14-phenyl-4-[4-)2-pyridinyl)benzyl]-3,8,11,13-tetraazatetradec-1-ylcarbamate;

methyl1-[({4-({3,3-dimethyl-2-[3-(2-methylbenzyl)-2-oxo-1-imidazolidinyl]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-({3,3-dimethyl-2-[3-(3-methylbenzyl)-2-oxo-1-imidazolidinyl]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-[(3,3-dimethyl-2-{3-[(2-methyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-phenyl-1-[4-(3-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-[(3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-1-[4-(6-methyl-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-[(3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-phenyl-1-[4-(3-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-{[2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-2-hydroxy-5-phenyl-1-[4-(3-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({3-hydroxy-4-({2-[3-(3-methoxybenzyl)-2-oxo-1-imidazolidinyl]-3,3-dimethylbutanoyl}amino)-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-{[2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-[(3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-phenyl-1-[4-(4-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-1-[4-(5-methyl-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({3-hydroxy-4-({2-[3-(2-methoxybenzyl)-2-oxo-1-imidazolidinyl]-3,3-dimethylbutanoyl}amino)-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-({3,3-dimethyl-2-[3-(2-methylbenzyl)-2-oxo-1-imidazolidinyl]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-({3,3-dimethyl-2-[3-(3-methylbenzyl)-2-oxo-1-imidazolidinyl]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({3-hydroxy-4-({2-[3-(2-methoxybenzyl)-2-oxo-1-imidazolidinyl]-3,3-dimethylbutanoyl}amino)-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({3-hydroxy-4-({2-[3-(3-methoxybenzyl)-2-oxo-1-imidazolidinyl]-3,3-dimethylbutanoyl}amino)-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-[(3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-1-[4-(4-methyl-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-{[2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-2-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-[(3,3-dimethyl-2-{3-[(2-methyl-3-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-[(3,3-dimethyl-2-{3-[(6-methyl-3-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-({3,3-dimethyl-2-[2-oxo-3-(3-pyridinylmethyl)-1-imidazolidinyl]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-({3,3-dimethyl-2-[2-oxo-3-(4-pyridinylmethyl)-1-imidazolidinyl]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-({3,3-dimethyl-2-[2-oxo-3-(2-pyridinylmethyl)-1-imidazolidinyl]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl7-benzyl-1,10-ditert-butyl-5-hydroxy-4-[4-(6-methyl-3-pyridinyl)benzyl]-2,9,12-trioxo-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl1-[({4-[(3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-1-[4-(6-methyl-3-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-[(3,3-dimethyl-2-{3-[(2-methyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-1-[4-(5-methyl-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl7-benzyl-1,10-ditert-butyl-5-hydroxy-4-[4-(5-methyl-2-pyridinyl)benzyl]-2,9,12-trioxo-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl1-[({4-[(3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2-methylbutylcarbamate;

methyl4-benzyl-1,10-ditert-butyl-5-hydroxy-7-[4-(5-methyl-2-pyridinyl)benzyl]-2,9,12-trioxo-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl1-[({4-{[2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-3-hydroxy-1-[4-(5-methyl-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({1-benzyl-4-[(3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-[4-(2-pyridinyl)phenyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl4-benzyl-10-tert-butyl-5-hydroxy-1-[1-methyl-1-((R)-methylsulfinyl)ethyl]-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl1-[({2-hydroxy-4-[(3-methyl-2-{3-[(1-methyl-1H-benzimidazol-2-yl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({2-hydroxy-4-[(2-{3-[(2-isopropyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}-3-methylpentanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({3-hydroxy-4-[(3-methyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-[(3,3-dimethyl-2-{3-[(1-methyl-1H-benzimidazol-2-yl)methyl]-2-oxo-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-[(3,3-dimethyl-2-{3-[(1-methyl-1H-benzimidazol-2-yl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({3-hydroxy-4-[(2-{3-[(2-isopropyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}-3,3-dimethylbutanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({2-hydroxy-4-[(2-{3-[(2-isopropyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}-3,3-dimethylbutanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl7-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-4-[4-(3-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl7-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-4-[4-(4-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl1-[({4-[(3,3-dimethyl-2-{3-[(2-methyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-[(3,3-dimethyl-2-{3-[(2-methyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-[(3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl7-benzyl-10-sec-butyl-1-tert-butyl-6-hydroxy-13-methyl-14-(2-methyl-1,3-thiazol-4-yl)-2,9,12-trioxo-4-[4-(2-pyridinyl)benzyl]-3,8,11,1 3-tetraazatetradec-1-ylcarbamate;

methyl7-benzyl-10-sec-butyl-1-tert-butyl-5-hydroxy-13-methyl-14-(2-methyl-1,3-thiazol-4-yl)-2,9,12-trioxo-4-[4-(2-pyridinyl)benzyl]-3,8,11,1 3-tetraazatetradec-1-ylcarbamate;

methyl1-[({4-{[2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

1,2,5,6-tetradeoxy-2,5-bis({2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-1,6-bis[4-(2-pyridinyl)phenyl]-D-iditol;

methyl1-[({4-[(3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-1-[4-(6-methoxy-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-{[2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-3-hydroxy-1-[4-(6-methoxy-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-[(2-{3-[(6-tert-butyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}-3,3-dimethylbutanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-4,7-bis[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl1-[({3-hydroxy-4-[(2-{3-[(6-isopropyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}-3,3-dimethylbutanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-[(2-{3-[(6-tert-butyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}-3,3-dimethylbutanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({-4-{[2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-2-hydroxy-1-[4-(6-methoxy-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl7-benzyl-1,10-ditert-butyl-5-hydroxy-4-[4-(6-methoxy-2-pyridinyl)benzyl]-2,9,12-trioxo-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl4-benzyl-1,10-ditert-butyl-5-hydroxy-7-[4-(6-methoxy-2-pyridinyl)benzyl]-2,9,12-trioxo-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl1-[({4-[(3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-1-[4-(6-methoxy-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-({2-[3-(2-aminobenzyl)-2-oxo-1-imidazolidinyl]-3,3-dimethylbutanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-({2-[3-(4-aminobenzyl)-2-oxo-1-imidazolidinyl]-3,3-dimethylbutanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-({2-[3-(3-aminobenzyl)-2-oxo-1-imidazolidinyl]-3,3-dimethylbutanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-[(3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-1-[4-(5-methyl-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({4-[(3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-1-[4-(5-methyl-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({3-hydroxy-4-[(2-{3-[(6-isopropyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}-3,3-dimethylbutanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl1-[({1-benzyl-4-[(3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-[4-(2-pyridinyl)phenyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl4-benzyl-1,10-disec-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl1-({[1-benzyl-2-hydroxy-4-({3-methyl-2-[2-oxo-3-(4-quinolinylmethyl)-1-imidazolidinyl]pentanoyl}amino)-5-phenylpentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1S,3S,4S)-4({(2S)-2-[3-(2-fluorobenzyl)-2-oxoimidazolidin-1-yl]-3,3-dimethylbutanoyl}amino)-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1S,3S,4S)-4({(2S)-2-[3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl]-3,3-dimethylbutanoyl}amino)-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl])amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1S,3S,4S)-4({(2S)-2-[3-(3-fluorobenzyl)-2-oxoimidazolidin-1-yl]-3,3-dimethylbutanoyl}amino)-3-hydroxy5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{2-oxo-3-[2-(trifluoromethyl)benzyl]imidazolidin-1-yl}butanoyl)amino]-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{2-oxo-3-[4-(trifluoromethyl)benzyl]imidazolidin-1-yl}butanoyl)amino]-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{2-oxo-3-[3-(trifluoromethyl)benzyl]imidazolidin-1-yl}butanoyl)amino]-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1S,3S,4S)-4({(2S)-2-[3-(2-amino-3-methylbenzyl)-2-oxoimidazolidin-1-yl]-3,3-dimethylbutanoyl}amino)-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S,4S,5S,7S,10S)-4benzyl-1 0-tert-butyl-5-hydroxy-2,9, 12-trioxo-7-(4-pyridin-2-ylbenzyl)-1-[(3R)-tetrahydrofuran-3-yl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1S)-1-({[(1S,3S,4S)-3-hydroxy-4-({(2S)-2-[3-(3-hydroxybenzyl)-2-oxoimidazolidin-1-yl]-3,3-dimethylbutanoyl}amino)-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1S,3S,4S)-3-hydroxy-4-({(2S)-2-[3-(4-hydroxybenzyl)-2-oxoimidazolidin-1-yl]-3,3-dimethylbutanoyl}amino)-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1S,3S,4S)-3-hydroxy-4-({(2S)-2-[3-(2-hydroxybenzyl)-2-oxoimidazolidin-1-yl]-3,3-dimethylbutanoyl}amino)-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S,4S,5S,7S,10S)-4benzyl-1,10-di-tert-butyl-5-hydroxy-2,9,12-trioxo-7-[7-(1,3-thiazol-2-yl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1S,4S,5S,7S,10S)-4benzyl-10-tert-butyl-5-hydroxy-1-[(1S)-1-methylpropyl]-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1S,4S,5S,7S,10S)-4benzyl-1,10-di-tert-butyl-5-hydroxy-2,9,12-trioxo-7-(4-pyridin-3-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1S)-1-({[(1S,3S,4S)-3-hydroxy-4-{[(2S)-2-methyl-3-(methylsulfonyl)propanoyl]amino}-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S,4S,5S,7S,10S)-4benzyl-1,10-di-tert-butyl-5-hydroxy-2,9,12-trioxo-7-4-pyridin-4-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1S)-1-({[(1S,3S,4S)-3-hydroxy-4-{[(2S)-2-hydroxy-3,3-dimethylbutanoyl]amino}-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S,4S,6S,7S,10S)-7-benzyl-1,10-di-tert-butyl-6-hydroxy-12,12-dioxido-2,9-dioxo-4-(4-pyridin-2-ylbenzyl)-12-thia-3,8,11-triazatridec-1-ylcarbamate;

methyl(1R,4S,5S,7S,10S)-4-benzyl-10-tert-butyl-5-hydroxy-1-[(methylthio)methyl]-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1R,4S,5S,7S,10S)-4-benzyl-10-tert-butyl-5-hydroxy-1-[(methylsulfonyl)methyl]-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1R)-1-{[((1S,2S,4S)-4-{[4(aminosulfonyl)benzoyl]amino}-1-benzyl-2-hydroxy-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1S,3S,4S)-3-hydroxy-4-{[(2R)-2-hydroxy-3-methyl-3-(methylsulfonyl)butanoyl]amino}-5-phenyl-1-(4pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1R,3S,4S)-4-[(4-chloro-2-methylbenzoyl)amino]-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1R,3S,4S)-3-hydroxy-4-[(4-methoxy-2-methylbenzoyl)amino]-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1R,3S,4S)-3-hydroxy-4-[(2-methylbenzoyl)amino]-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1R,3S,4S)-4-{[(2S)-3,3-dimethyl-2-(2-oxoimidazolidin-1-yl)butanoyl]amino}-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1R,3 S,4S)-3-hydroxy-4-{[(2S,3S)-3-methyl-2-(2-oxoimidazolidin-1-yl)pentanoyl]amino}-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-{[((1S,2S,4S)-4-{[3-(aminosulfonyl)benzoyl]amino}-1-benzyl-2-hydroxy-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1S,3S,4S)-4-[(3-chloro-2-methylbenzoyl)amino]-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1S,3S,4S)-3-hydroxy-4-[(3-hydroxy-2-methylbenzoyl)amino]-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1S,3S,4S)-3-hydroxy-4-{[(3-methylisoxazol-4-yl)carbonyl]amino}-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1S,3S,4S)-4-{[(3,5-dimethylisoxazol-4-yl)carbonyl]amino}-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S,4S,5S,7S,10S)-4benzyl-10-tert-butyl-5-hydroxy-1-isobutyl-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1S,4S,5S,7S,10S)-1-(2-amino-2-oxoethyl)-4-benzyl-10-tert-butyl-5-hydroxy-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl2-{[(1S,2S,4S)-1-benzyl-2-hydroxy-4-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-5-(4-pyridin-2-ylphenyl)pentyl]amino}-1-[(methoxycarbonyl)amino]-2-oxoethylcarbamate;

methyl(1S,4S,6S,7S,10S)-7-benzyl-1,10-di-tert-butyl-6-hydroxy-2,9,12,14-tetraoxo-4-(-4-pyridin-2-ylbenzyl)-15-oxa-3,8,11,13-tetraazahexadec-1-ylcarbamate;

methyl(1S,4S,6S,7S,10S)-7-benzyl-1,10-di-tert-butyl-6-hydroxy-14,14-dimethyl-2,9,12,15-tetraoxo-4-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazahexadec-1-ylcarbamate;

(4S,7S,8S,10S,13S)-7-benzyl-4,13-di-tert-butyl-8-hydroxy-2,5,12,15-tetraoxo-10-(4-pyridin-2-ylbenzyl)-16-oxa-3,6,11,14-tetraazaheptadec-1-ylacetate;

methyl(1S)-1-({[(1S,3S,4S)-4-{[(2S)-2-(glycoloylamino)-3,3-dimethylbutanoyl]amino}-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

(3S,6S,7S,9S,12S)-6-benzyl3-[(tert-butoxycarbonyl)amino]-12-tert-butyl-7-hydroxy-2,2-dimethyl-4,11,14-trioxo-9-(4-pyridin-2-ylbenzyl)-15-oxa-5,10,13-triazahexadec-1-ylacetate;

methyl(1S,4S,5S,7S,10S)-4benzyl-10-tert-butyl-5-hydroxy-1-(2-hydroxy-1,1-dimethylethyl)-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1S,4S,5S,7S,10S)-1-{[(aminocarbonyl)amino]methyl}-4-benzyl-10-tert-butyl-5-hydroxy-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1S,4S,5S,7S,10S)-4benzyl-10-tert-butyl-5-hydroxy-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-1-(pyridin-2-ylmethyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1S,4S,5S,7S,10S)-4benzyl-10-tert-butyl-5-hydroxy-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-1-(1,3-thiazol-4-ylmethyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

(3S,6S,7S,9S,12S)-6-benzyl-12-tert-butyl-7-hydroxy-3-[(methoxycarbonyl)amino]-2,2-dimethyl-4,11,14-trioxo-9-(4-pyridin-2-ylbenzyl)-15-oxa-5,10,13-triazahexadec-1-ylacetate;

methyl(1S,4R,6S,7S,10S)-7-benzyl1,10-di-tert-butyl-6-hydroxy-15,15-dioxido-2,9-dioxo-4-(4-pyridin-2-ylbenzyl)-15-thia-3,8,11,14tetraazahexadec-1-ylcarbamate;

methyl(1S,4R,6S,7S,10S)-7-benzyl 1,10-di-tert-butyl-6-hydroxy-2,9,15-trioxo-4-(4-pyridin-2-ylbenzyl)-16-oxa-3,8,11,14-tetraazaheptadec-1-ylcarbamate;

methyl(1S)-1-({[(1R,3S,4S)-4-{[(2S)-2-(1,1-dioxido-1,2,5-thiadiazolidin-2-yl)-3,3-dimethylbutanoyl]amino}-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(5S,8S,10S,11S,14S)-11-benzyl-5-tert-butyl-10-hydroxy-14-[(methoxycarbonyl)amino]-15-methyl-3,6,13-trioxo-8-(4-pyridin-2-ylbenzyl)-2-oxa-4,7,12-triazahexadecan-16-oate;

methyl(5S,8S,10S,11S,14S)-11-benzyl-5-tert-butyl-10-hydroxy-14-[(methoxycarbonyl)amino]-15,15-dimethyl-3,6,13-trioxo-8-(4-pyridin-2-ylbenzyl)-2-oxa-4,7,12-triazahexadecan-16-oate;

methyl(1S)-1-[({((1S,2S,4S)-1-benzyl-2-hydroxy-5-phenyl-4-[(thien-2-ylcarbonyl)amino]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,2S,4S)-1-benzyl-2-hydroxy-5-phenyl-4-[(thien-3-ylcarbonyl)amino]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-{[((1S,2S,4S)-1-benzyl-2-hydroxy-4-{[(3-methylthien-2-yl)carbonyl]amino}-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamate;

methyl(1S)-1-{[((1S,2S,4S)-1-benzyl-2-hydroxy-4-{[(5-methylthien-2-yl)carbonyl]amino}-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamate;

methyl(1S)-1-{[((1S,2S,4S)-1-benzyl-2-hydroxy-4-{[(1-methyl-1H-pyrrol-2-yl)carbonyl]amino}-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamate;

methyl(1S)-1-{[((1S,2S,4S)-1-benzyl-4-{[(3,5-dimethylisoxazol-4-yl)carbonyl]amino}-2-hydroxy-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1S,3S,4S)-4-{[(2S)2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-5-phenyl-3-(phosphonooxy)-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1R,3S,4S)-4-{[(2S)2-(3-{[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]methyl}-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-5-phenyl-3-(phosphonooxy)-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

(1S,3S)-1-((1S)-1-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-2-phenylethyl)-3-({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-4-(4-pyridin-2-ylphenyl)butyl(2S)-2-aminopropanoate;

methyl(1S)-1-({[(1R,3S,4S)-4{(2S)-3,3-dimethyl-2-[3-({6-[1-methyl-1-(phosphonooxy)ethyl]pyridin-2-yl}methyl)-2-oxoimidazolidin-1-yl]butanoyl}amino)-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

(3S,5S,8S)-34(1S)-1-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-2-phenylethyl)-8-tert-butyl-7,10-dioxo-5-(4-pyridin-2-ylbenzyl)-2,11-dioxa-6,9-diazadodec-1-yl(dimethylamino)acetate;

(1S,3S)-1-((1S)-1-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-2-phenylethyl)-3-({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-4-(4-pyridin-2-ylphenyl)butyl(phosphonooxy)methylcarbonate;

(5S,7S,10S)-5(1S)-1-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-2-phenylethyl)-10-tert-butyl-3,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-2,4,13-trioxa-8,11-diazatetradec-1-yl(dimethylamino)acetate;

(5S,8S,10S)-10-((1S)-1-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-2-phenylethyl)-5-tert-butyl-3,6,12-trioxo-8-(4-pyridin-2-ylbenzyl)-2,11-dioxa-4,7-diazapentadecan-15-oicacid;

(1S,3S)-1-((1S)-1-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-2-phenylethyl)-3-({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-4-(4-pyridin-2-ylphenyl)butyl{[ethoxy(hydroxy)phosphoryl]oxy}methyl carbonate;

methyl(1S,4S,6S)-64(1S)-1-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-2-phenylethyl)-1-tert-butyl-10-hydroxy-10-oxido-2-oxo-4-(4-pyridin-2-ylbenzyl)-7,9,11-trioxa-3-aza-10-phosphatridec-1-ylcarbamate;

methyl(1S,4S,6S)-64(1S)-1-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-3,3-dimethylbutanoyl]amino}-2-phenylethyl)-1-tert-butyl-10,10-dihydroxy-10-oxido-2-oxo-4-(4-pyridin-2-ylbenzyl)-7,9-dioxa-3-aza-10-phosphadec-1-ylcarbamate;

methyl(1S,4S,5S,7S,10S)-4benzyl-1,10-bis(tert-butyl)-2,9,12-trioxo-5-(phosphonooxy)-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1S,4S,5S,7S,10S)-7-benzyl-1,10-bis(tert-butyl)-2,9,12-trioxo-5-[(phosphonooxy)methoxy]-4-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1S,4S,5S,7S,10S)-4benzyl-1,10-bis(tert-butyl)-2,9,12-trioxo-5-[(phosphonooxy)methoxy]-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,1-triazatetradec-1-ylcarbamate;

methyl(1S,4S,6S)-64(1S)-1-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-ylcarbamate;dimethylbutanoyl]amino}-2-phenylethyl)-1-tert-butyl-10,10-dihydroxy-8-methyl-10-oxido-2-oxo-4-(4-pyridin-2-ylbenzyl)-7,9-dioxa-3-aza-10-phosphadec-1-ylcarbamate;

methyl(1S,4S,5S)-4-benzyl-1-tert-butyl-5-{(2S)-2-[((2S)-3,3-dimethyl-2-{3-[(6-methylpyridin-2-yl)methyl]-2-oxoimidazolidin-1-yl}butanoyl)amino]-3-phenylpropyl}-9,9-dihydroxy-9-oxido-2-oxo-6,8-dioxa-3-aza-9-phosphanon-1-ylcarbamate;

methyl(1S,4S,5S,7S,10S)-4benzyl-1,10-bis(tert-butyl)-2,9,12-trioxo-5-[1-(phosphonooxy)ethoxy]-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;and

methyl(1S)-3-amino-1-({[(1S,2S,4S)-1-benzyl-2-hydroxy-4-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-5-(4-pyridin-2-ylphenyl)pentyl]amino}carbonyl)-2,2-dimethyl-3-oxopropylcarbamate;or a pharmaceutical acceptable salt form, prodrug or stereoisomerthereof.

In a second embodiment, the present invention provides a compound offormula (II)

or a pharmaceutically acceptable salt form, prodrug, or stereoisomerthereof, wherein:

-   R^(A) is —N(H)C(O)R⁸, —O(R_(a)), —OC(O)OR_(a), —NR_(a)R_(b),    —N(R_(b))S(O)₂R_(a), —N(R_(b))alkylN(R_(b))S(O)₂R_(a),    —N(R_(b))alkylN(R_(b))C(O)OR_(a),    —N(R_(b))alkylN(R_(b))C(O)NR_(a)R_(b), -alkylSR_(a), -alkylS(O)R_(a)    or -alkylS(O)₂R_(a);-   R¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,    heterocycle, aryl or heteroaryl; wherein each R¹ is substituted with    0, 1 or 2 substituents independently selected from the group    consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl,    hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),    —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂, and    R^(1a);-   R^(1a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(1a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R² is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,    heterocycle, aryl or heteroaryl; wherein each R² is substituted with    0, 1 or 2 substituents independently selected from the group    consisting of halo, —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a),    —NR_(a)R_(b), —NR_(b)C(O)R_(a), —N(R_(b))C(O)OR_(a),    —N(R_(a))C(═N)NR_(a)R_(b), —N(R_(a))C(O)NR_(a)R_(b),    —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(2a);-   R^(2a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(2a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R³ is alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, -alkylOR_(a),    -alkylSR_(a), -alkylSOR_(a), -alkylSO₂R_(a), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)OR_(a),    -alkylN(R_(a))C(═N)NR_(a)R_(b), -alkylN(R_(a))C(O)NR_(a)R_(b),    -alkylC(O)NR_(a)R_(b), -alkylC(O)OR_(a), cycloalkyl,    cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle,    heterocyclealkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;    wherein the cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl,    cycloalkyl moiety of the cycloalkylalkyl, cycloalkenyl moiety of the    cycloalkenylalkyl, heterocycle moiety of the heterocyclealkyl,    heteroaryl moiety of the heteroarylalkyl and the aryl moiety of the    arylalkyl are independently substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and    R^(3a);-   R^(3a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(3a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    oxo, alkyl, alkenyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), and -alkylC(O)N(alkyl)₂;-   R⁴ is H and R⁵ is OR¹⁶; or-   R⁵ is H and R⁴ is OR¹⁶; or-   R⁴ and R⁵ are —OR¹⁶;-   R⁶ is alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, -alkylOR_(a),    -alkylSR_(a), -alkylSOR_(a), -alkylSO₂R_(a), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)OR_(a),    -alkylN(R_(a))C(═N)NR_(a)R_(b), -alkylN(R_(a))C(O)NR_(a)R_(b),    -alkylC(O)NR_(a)R_(b), -alkylC(O)OR_(a), cycloalkyl,    cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle,    heterocyclealkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;    wherein the cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl,    cycloalkyl moiety of the cycloalkylalkyl, cycloalkenyl moiety of the    cycloalkenylalkyl, heterocycle moiety of the heterocyclealkyl,    heteroaryl moiety of the heteroarylalkyl and the aryl moiety of the    arylalkyl are independently substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and    R^(6a);-   R^(6a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(6a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    oxo, alkyl, alkenyl, hydroxy, alkoxy, —NH₂, N(H)(alkyl), —N(alkyl)₂,    —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl,    —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH,    —C(O)Oalkyl, —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), and -alkylC(O)N(alkyl)₂;-   R⁷ is —N(R_(b))C(O)OR_(a), alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, heterocycle, aryl or heteroaryl; wherein the alkyl,    alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl and    heteroaryl are independently substituted with 0, 1 or 2 substituents    independently selected from the group consisting of halo, —OR_(a),    OC(O)R_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —NR_(a)R_(b),    —N(R_(b))C(O)R_(a), —N(R_(b))C(O)OR_(a), —N(R_(a))C(═N)NR_(a)R_(b),    —N(R_(a))C(O)NR_(a)R_(b), —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(7a);-   R^(7a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(7a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R⁸ is —OR_(a), —NR_(a)R_(b), —N(R_(b))C(O)OR_(a), -alkylOR_(a),    -alkylOC(O)R_(a), or —O-alkylC(O)R_(a);-   R¹⁶ is hydrogen or R¹⁵;-   R¹⁵ is

-   R₁₀₃ is C(R₁₀₅)₂, O or —N(R₁₀₅);-   R₁₀₄ is hydrogen, alkyl, haloalkyl, alkoxycarbonyl, aminocarbonyl,    alkylaminocarbonyl or dialkylaminocarbonyl,-   each M is independently selected from the group consisting of H,    —N(R₁₀₅)₂, alkyl, alkenyl, and R₁₀₆; wherein 1 to 4—CH₂ radicals of    the alkyl or alkenyl, other than the —CH₂ radical that is bound to    Z, is optionally replaced by a heteroatom group selected from the    group consisting of O, S, S(O), SO₂ and N(R₁₀₅); and wherein any    hydrogen in said alkyl, alkenyl or R₁₀₆ is optionally replaced with    a substituent selected from the group consisting of oxo, —OR₁₀₅,    —R₁₀₅, —N(R₁₀₅)₂, —CN, —C(O)OR₁₀₅, —C(O)N(R₁₀₅)₂, —SO₂N(R₁₀₅),    —N(R₁₀₅)C(O)R₁₀₅, —C(O)R₁₀₅, —SR₁₀₅, —S(O)R₁₀₅, —SO₂R₁₀₅, —OCF₃,    —SR₁₀₆, —SOR₁₀₆, —SO₂R₁₀₆, —N(R₁₀₅)SO₂R₁₀₅, halo, —CF₃, NO₂ and    phenyl; provided that when M is —N(R₁₀₅)₂, Z, and Z₂ are —CH₂;-   Z₁ is CH₂, O, S, —N(R₁₀₅), or, when M is absent, H;-   Z₂ is CH₂, O, S or —N(R₁₀₅);-   Q is O or S;-   W is P or S; wherein when W is S, Z₁ and Z₂ are not S;-   M′ is H, alkyl, alkenyl or R₁₀₆; wherein 1 to 4—CH₂ radicals of the    alkyl or alkenyl is optionally replaced by a heteroatom group    selected from O, S, S(O), SO₂, or N(R₁₀₅); and wherein any hydrogen    in said alkyl, alkenyl or R₁₀₆ is optionally replaced with a    substituent selected from the group consisting of oxo, —OR₁₀₅,    —R₁₀₅, —N(R₁₀₅)₂, —CN, —C(O)OR₁₀₅, —C(O)N(R₁₀₅)₂, —SO₂N(R₁₀₅),    —N(R₁₀₅)C(O)R₁₀₅, —C(O)R₁₀₅, —SR₁₀₅, —S(O)R₁₀₅, —SO₂R₁₀₅, —OCF₃,    —SR₁₀₆, —SOR₁₀₆, SO₂R₁₀₆, —N(R₁₀₅)SO₂R₁₀₅, halo, —CF₃ and NO₂;-   R₁₀₆ is a monocyclic or bicyclic ring system selected from the group    consisting of aryl, cycloalkyl, cycloalkenyl heteroaryl and    heterocycle; wherein any of said heteroaryl and heterocycle ring    systems contains one or more heteroatoms selected from the group    consisting of O, N, S, SO, SO₂ and N(R₁₀₅); and wherein any of said    ring system is substituted with 0, 1, 2, 3, 4, 5 or 6 substituents    selected from the group consisting of hydroxy, alkyl, alkoxy, and    —OC(O)alkyl;-   each R₁₀₅ is independently selected from the group consisting of H    or alkyl; wherein said alkyl is optionally substituted with a ring    system selected from the group consisting of aryl, cycloalkyl,    cycloalkenyl, heteroaryl and heterocycle; wherein any of said    heteroaryl and heterocycle ring systems contains one or more    heteroatoms selected from the group consisting of O, N, S, SO, SO₂,    and N(R₁₀₅); and wherein any one of said ring systems is substituted    with 0, 1, 2, 3 or 4 substituents selected from the group consisting    of oxo, —OR₁₀₅, —R₁₀₅, —N(R₁₀₅)₂, —N(R₁₀₅)C(O)R₁₀₅, —CN, —C(O)OR₁₀₅,    —C(O)N(R₁₀₅)₂, halo and —CF₃;-   each R₁₀₇ and R₁₀₈ are independently selected from the group    consisting of hydrogen and alkyl;-   q is 0 or 1;-   m is 0 or 1;-   m′ is 0 or 1;-   m″ is 0 or 1;-   r is 0, 1, 2, 3 or 4;-   t is 0 or 1;-   R_(a) and R_(b) at each occurrence are independently selected from    the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    cycloalkyl, aryl, heteroaryl and heterocycle; wherein each R_(a) and    R_(b), at each occurrence, is independently substituted with 0, 1, 2    or 3 substituents independently selected from the group consisting    of cyano, nitro, halo, oxo, hydroxy, alkoxy, alkyl, alkenyl,    alkynyl, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),    —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and R_(c);-   alternatively, R_(a) and R_(b), together with the nitrogen atom to    which they are attached, form a ring selected from the group    consisting of heteroaryl and heterocycle; wherein each of the    heteroaryl and heterocycle is independently substituted with 0, 1, 2    or 3 substituents independently selected from the group consisting    of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo,    hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),    —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, formylalkyl,    nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH₂,    -alkylN(H)(alkyl), -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂,    -alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH,    -alkylC(O)Oalkyl, -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl),    -alkylC(O)N(alkyl)₂ and R_(c); and-   R_(c) is aryl, heteroaryl or heterocycle; wherein each R_(c) is    independently substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of halo, nitro,    oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkyl-NH₂, -alkyl-N(H)(alkyl), -alkyl-N(alkyl)₂,    -alkyl-N(H)C(O)NH₂, -alkyl-N(H)C(O)N(H)(alkyl),    -alkyl-N(H)C(O)N(alkyl)₂, -alkyl-C(O)OH, -alkyl-C(O)Oalkyl,    -alkyl-C(O)NH₂, -alkyl-C(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂.

For example, the present invention provides a compound of formula (II)wherein R⁴ is H; R⁵ is OR¹⁶; and R^(A), R¹, R^(1a), R², R^(2a), R³,R^(3a), R⁶, R^(6a), R⁷, R^(7a), R⁸, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q,m, m′, m″, r, t, R_(a), R_(b), and R_(c) are as defined in formula (II).

For example, the present invention provides a compound of formula (II)wherein R⁴ is OR¹⁶ and R⁵ is H; and R^(A), R¹, R^(1a), R², R^(2a), R³,R^(3a), R⁶, R^(6a), R⁷, R^(7a), R⁸, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁,Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t R_(a), R_(b) andR_(c) are as defined in formula (II).

For example, the present invention provides a compound of formula (II)wherein R⁴ is H; R⁵ is OR¹⁶; R² is alkyl; and R^(A), R¹, R^(1a), R³,R^(3a), R⁶, R^(1a), R⁷, R^(7a), R⁸, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁,Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), andR_(c) are as defined in formula (II).

For example, the present invention provides a compound of formula (II)wherein R⁴ is OR¹⁶; R⁵is H; R²is alkyl; and R^(A), R¹, R^(1a), R^(2a),R³, R^(3a), R⁶, R^(6a), R⁷, R^(7a), R⁸, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M,Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b),and R_(c) are as defined in formula (II).

For example, the present invention provides a compound of formula (II)wherein R⁴ is H; R⁵ is OR¹⁵; R² is alkyl; R³ is arylalkyl wherein thearyl moiety of the arylalkyl is substituted with 0, 1, 2, 3 or 4substituents independently selected from the group consisting of cyano,halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,—N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,—N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),—N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂, —C(O)N(H)(alkyl),—C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH₂,alkylN(H)(alkyl), -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂,-alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH,-alkylC(O)Oalkyl, -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl),-alkylC(O)N(alkyl)₂ and R^(3a); and R^(A), R¹, R^(1a), R^(3a), R⁶,R^(6a), R⁷, R^(7a), R⁸, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z, Q, W, M, Z₁,Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), andR_(c) are as defined in formula (II).

For example, the present invention provides a compound of formula (II)wherein R⁴ is OR¹⁶; R⁵ is H; R² is alkyl; R³ is arylalkyl wherein thearyl moiety of the arylalkyl is substituted with 0, 1, 2, 3 or 4substituents independently selected from the group consisting of cyano,halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,—N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,—N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),—N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂, —C(O)N(H)(alkyl),—C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylNH₂,-alkylN(H)(alkyl), -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂,-alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH,-alkylC(O)Oalkyl, -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl),-alkylC(O)N(alkyl)₂ and R^(3a); and R^(A), R¹, R^(1a), R^(3a), R⁶,R^(6a), R⁷, R^(7a), R⁸, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′,R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), and R_(c) are asdefined in formula (II).

For example, the present invention provides a compound of formula (II)wherein R⁴ is H; R⁵ is OR¹⁶; R²is alkyl; R³ is arylalkyl wherein thearyl moiety of the arylalkyl is unsubstituted or substituted with oneR^(3a); and R^(A), R¹, R^(1a), R^(3a), R⁶, R^(6a), R⁷, R^(7a), R⁸, R¹⁵,R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′,m″, r, t, R_(a), R_(b), and R_(a) are as defined in formula (II).

For example, the present invention provides a compound of formula (II)wherein R⁴ is OR¹⁶; R⁵is H; R² is alkyl; R³ is arylalkyl wherein thearyl moiety of the arylalkyl is unsubstituted or substituted with oneR^(3a); and R^(A), R¹, R^(1a), R^(3a), R⁶, R^(6a), R⁷, R^(7a), R⁸, R¹⁵,R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′,m″, r, t, R_(a), R_(b), and R_(c) are as defined in formula (II).

For example, the present invention provides a compound of formula (II)wherein R⁴is H; R⁵is OR¹⁶; R² is alkyl; R³ is arylalkyl wherein the arylmoiety of the arylalkyl is unsubstituted or substituted with one R^(3a);R^(3a) is unsubstituted or substituted aryl or unsubstituted orsubstituted heteroaryl; and R^(A), R¹, R^(1a), R⁶, R^(6a), R⁷, R^(7a),R⁸, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄ , R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈,q, m, m′, m″, r, t, R_(a), R_(b), R_(c) and the substituents of R^(3a)are as defined in formula (II).

For example, the present invention provides a compound of formula (II)wherein R⁴ is OR¹⁶; R⁵ is H; R² is alkyl; R³ is arylalkyl wherein thearyl moiety of the arylalkyl is unsubstituted or substituted with oneR^(3a); R^(3a) is unsubstituted or substituted aryl or unsubstituted orsubstituted heteroaryl; and R^(A), R¹, R^(1a), R⁶, R^(6a), R⁷, R^(7a),R⁸, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R¹⁰⁵, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈,q, m, m′, m″, r, t, R_(a), R_(b), R_(c) and the substituents of R^(3a)are as defined in formula (II).

For example, the present invention provides a compound of formula (II)wherein R⁴ is H; R⁵ is OR¹⁶; R² is alkyl; R³ is arylalkyl wherein thearyl moiety of the arylalkyl is unsubstituted or substituted with oneR^(3a); R^(3a) is unsubstituted or substituted aryl, or unsubstituted orsubstituted heteroaryl; R⁶ is unsubstituted or substituted arylalkyl;and R^(A), R¹, R^(1a), R⁷, R^(7a), R⁸, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M,Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b),substituents of R^(3a) and R⁶ are as defined in formula (II).

For example, the present invention provides a compound of formula (II)wherein R⁴ is OR¹⁶; R⁵ is H; R² is alkyl; R³ is arylalkyl wherein thearyl moiety of the arylalkyl is unsubstituted or substituted with oneR^(3a); R^(3a) is unsubstituted or substituted aryl, or unsubstituted orsubstituted heteroaryl; R⁶ is unsubstituted or substituted arylalkyl;and R^(A), R¹, R^(1a), R⁷, R^(7a), R⁸, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M,Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇ , R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b),R_(c), and the substituents of R^(3a) and R⁶ are as defined in formula(II).

For example, the present invention provides a compound of formula (II)wherein R⁴ is H; R⁵ is OR¹⁶; R² is alkyl; R³ is arylalkyl wherein thearyl moiety of the arylalkyl is unsubstituted or substituted with oneR^(3a); R^(3a) is unsubstituted or substituted aryl, or unsubstituted orsubstituted heteroaryl; R⁶ is unsubstituted or substituted arylalkyl; R⁷is —N(R_(b))C(O)OR_(a), alkyl or heterocycle wherein the alky andheterocycle are independently substituted with 0, 1 or 2 substituentsindependently selected from the group consisting of halo, —OR_(a),—OC(O)R_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —NR_(a)R_(b),—N(R_(b))C(O)R_(a), —N(R_(b))C(O)OR_(a), —N(R_(a))C(═N)NR_(a)R_(b),—N(R_(a))C(O)NR_(a)R_(b), —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(7a); andR^(A), R¹, R⁷, R^(7a), R⁸, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W,M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(a) and thesubstituents of R^(3a) and R⁶ are as defined in formula (II).

For example, the present invention provides a compound of formula (II)wherein R⁴ is OR¹⁶; R⁵ is H; R² is alkyl; R³ is arylalkyl wherein thearyl moiety of the arylalkyl is unsubstituted or substituted with oneR^(3a); R^(3a) is unsubstituted or substituted aryl, or unsubstituted orsubstituted heteroaryl; R⁶ is unsubstituted or substituted arylalkyl; R⁷is —N(R_(b))C(O)OR_(a), alkyl or heterocycle wherein the alky andheterocycle are independently substituted with 0, 1 or 2 substituentsindependently selected from the group consisting of halo, —OR_(a),—OC(O)R_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —NR_(a)R_(b),—N(R_(b))C(O)R_(a), —N(R_(b))C(O)OR_(a), —N(R_(a))C(═N)NR_(a)R_(b),—N(R_(a))C(O)NR_(a)R_(b), —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(7a); andR^(A), R¹, R^(1a), R^(7a), R⁸, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z, Q, W,M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b),R_(c) and the substituents of R^(3a) and R⁶ are as defined in formula(II).

For example, the present invention provides a compound of formula (II)wherein R⁴ is H; R⁵ is OR¹⁶; R² is alkyl; R³ is arylalkyl wherein thearyl moiety of the arylalkyl is unsubstituted or substituted with oneR^(3a); R^(3a) is unsubstituted or substituted aryl, or unsubstituted orsubstituted heteroaryl; R⁶ is unsubstituted or substituted arylalkyl; R⁷is —N(R_(b))C(O)OR_(a), alkyl or heterocycle wherein the alky andheterocycle are independently substituted with 0, 1 or 2 substituentsindependently selected from the group consisting of halo, —OR_(a),—OC(O)R_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —NR_(a)R_(b),—N(R_(b))C(O)R_(a), —N(R_(b))C(O)OR_(a), —N(R_(a))C(═N)NR_(a)R_(b),—N(R_(a))C(O)NR_(a)R_(b), —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(7a); R¹is alkyl; and R^(A), R^(7a), R⁸, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂,Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c) andthe substituents of R^(3a) and R⁶ are as defined in formula (II).

For example, the present invention provides a compound of formula (II)wherein R⁴ is OR¹⁶; R⁵ is H; R² is alkyl; R³ is arylalkyl wherein thearyl moiety of the arylalkyl is unsubstituted or substituted with oneR^(3a); R^(3a) is unsubstituted or substituted aryl, or unsubstituted orsubstituted heteroaryl; R⁶ is unsubstituted or substituted arylalkyl; R⁷is —N(R_(b))C(O)OR_(a), alkyl or heterocycle wherein the alky andheterocycle are independently substituted with 0, 1 or 2 substituentsindependently selected from the group consisting of halo, —OR_(a),—OC(O)R_(a), —SR_(a),  SOR_(a), —SO₂R_(a), NR_(a)R_(b),—N(R_(b))C(O)R_(a), —N(R_(b)C(O)OR) _(a), —N(R_(a))C(═N)NR_(a)R_(b),—N(R_(a))C(O)NR_(a)R_(b), —C(O)NR_(a)R_(b), —C(O)OR_(a), and R^(7a); R¹is alkyl; and R^(A), R^(7a), R⁸, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂,Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c), andthe substituents of R^(3a) and R⁶ are as defined in formula (II).

For example, the present invention provides a compound of formula (II)wherein R⁴ is H; R⁵ is OR¹⁶; R² is alkyl; R³ is arylalkyl wherein thearyl moiety of the arylalkyl is unsubstituted or substituted with oneR^(3a); R^(3a) is unsubstituted or substituted aryl, or unsubstituted orsubstituted heteroaryl; R⁶ is unsubstituted or substituted arylalkyl; R⁷is —N(R_(b))C(O)OR_(a), alkyl or heterocycle wherein the alky andheterocycle are independently substituted with 0, 1 or 2 substituentsindependently selected from the group consisting of halo, —OR_(a),—OC(O)R_(a), —SR_(a), ≧SOR_(a), —SO₂R_(a), —NR_(a)R_(b),—N(R_(b))C(O)R_(a), —N(R_(b))C(O)OR_(a), —N(R_(a))C(═N)NR_(a)R_(b) ,—N(R_(a))C(O)NR_(a)R_(b), —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(7a); R¹is alkyl; Z₁ and Z₂ are O; Q is O; W is P; and R^(A), R^(7a), R⁸, R¹⁵,R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t,R_(a), R_(b), R_(c) and the substituents of R^(3a) and R⁶ are as definedin formula (II).

For example, the present invention provides a compound of formula (II)wherein R⁴ is OR¹⁶; R⁵ is H; R² is alkyl; R³ is arylalkyl wherein thearyl moiety of the arylalkyl is unsubstituted or substituted with oneR^(3a); R^(3a) is unsubstituted or substituted aryl, or unsubstituted orsubstituted heteroaryl; R⁶ is unsubstituted or substituted arylalkyl; R⁷is —N(R_(b))C(O)OR_(a), alkyl or heterocycle wherein the alky andheterocycle are independently substituted with 0, 1 or 2 substituentsindependently selected from the group consisting of halo, —OR_(a),—OC(O)R_(a), −SR_(a), —SOR_(a), —SO₂R_(a), —NR_(a)R_(b),—N(R_(b))C(O)R_(a), —N(R_(b))C(O)OR_(a), N(R_(a))C(═N)NR_(a)R_(b),—N(R_(a))C(O)NR_(a)R_(b), —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(7a); R¹is alkyl; Z₁ and Z₂ are O; Q is O; W is P; and R^(A), R^(7a), R⁸, R¹⁵,R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t,R_(a), R_(b), R_(c) and the substituents of R^(3a) and R⁶ are as definedin formula (II).

For example, the present invention provides a compound of formula (II)wherein R⁴ is H; R⁵ is OR¹⁶; R² is C1, C2, C3, C4 or C5 alkyl; R³ isphenylmethyl wherein the phenyl moiety the phenylmethyl is unsubstitutedor substituted with one R^(3a); R^(3a) is unsubstituted or substitutedaryl, or unsubstituted or substituted heteroaryl; R⁶ is unsubstituted orsubstituted phenylmethyl; R⁷ is —N(R_(b))C(O)OR_(a), C1-C5 alkyl orheterocycle wherein each of the C1-C5 alky and heterocycle areindependently substituted with 0, 1 or 2 substituents independentlyselected from the group consisting of halo, —OR_(a), —OC(O)R_(a),—SR_(a), —SOR_(a), —SO₂R_(a), —NR_(a)R_(b), —N(R_(b))C(O)R_(a),—N(R_(b))C(O)OR_(a), —N(R_(a))C(═N)NR_(a)R_(b),—N(R_(a))C(O)NR_(a)R_(b), —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(7a),wherein R_(a) and R_(b) are independently selected from the groupconsisting of hydrogen and C1-C5 alkyl; R¹ is C1, C2, C3, C4 or C5alkyl; Z, and Z₂ are O; Q is O; W is P; and R^(A), R^(7a), R⁸, R¹⁵, R¹⁶,R₁₀₃, R₁₀₄, R₁₀₅, M, M′, R₁₀₆, R₁₀₇, R₁₀₅, q, m, m′, m″, r, t, R_(c) andthe substituents of R^(3a) and R⁶ are as defined in formula (II).

For example, the present invention provides a compound of formula (II)wherein R⁴ is OR¹⁶; R⁵ is H; R² is C1, C2, C3, C4 or C5 alkyl; R³ isphenylmethyl wherein the phenyl moiety of the phenylmethyl isunsubstituted or substituted with one R^(3a); R^(3a) is unsubstituted orsubstituted aryl, or unsubstituted or substituted heteroaryl; R⁶ isunsubstituted or substituted arylalkyl; R⁷ is —N(R_(b))C(O)OR_(a), C1-C5alkyl or heterocycle wherein the each of the C1-C5 alky and heterocycleare independently substituted with 0, 1 or 2 substituents independentlyselected from the group consisting of halo, —OR_(a), —OC(O)R_(a),—SR_(a), —SOR_(a), —SO₂R_(a), —NR_(a)R_(b), —N(R_(b))C(O)R_(a),—N(R_(b))C(O)OR_(a), —N(R_(a))C(═N)NR_(a)R_(b),—N(R_(a))C(O)NR_(a)R_(b), —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(7a),wherein R_(a) and R_(b) are independently selected from the groupconsisting of hydrogen and C1-C5 alkyl; R¹ is C1, C2, C3, C4 or C5alkyl; Z₁ and Z₂ are O; Q is O; W is P; and R^(A), R^(7a), R⁸, R¹⁵, R¹⁶,R₁₀₃, R₁₀₄, R₁₀₅, M, M′, R₁₀₆, q, m, m′, m″, r, t, R_(c) and thesubstituents of R^(3a) and R^(6a) are as defined in formula (II).

For example, the present invention provides a compound of formula (II)wherein R⁴ is H; R⁵ is OR¹⁶; R² is C1, C2, C3, C4 or C5 alkyl; R³ isphenylmethyl wherein the phenyl moiety of the phenylmethyl isunsubstituted or substituted with one R^(13a); R^(3a) is unsubstitutedor substituted pyridyl; R⁶ is unsubstituted or substituted phenylmethyl;R⁷ is —N(R_(b))C(O)OR_(a), C1-C5 alkyl or tetrahydrofuranyl wherein eachof the C1-C5 alky is independently substituted with 0, 1 or 2substituent selected from the group consisting of halo, —OR_(a),—OC(O)R_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —NR_(a)R_(b),—N(R_(b))C(O)R_(a), —N(R_(b))C(O)OR_(a), —N(R_(a))C(═N)NR_(a)R_(b),—N(R_(a))C(O)NR_(a)R_(b), C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(7a),wherein R_(a) and R_(b) are independently selected from the groupconsisting of hydrogen and C1-C5 alkyl and R^(7a) is unsubstituted orsubstituted pyridyl or unsubstituted or substituted thiazolyl; R¹ isC1-C5 alkyl; Z₁ and Z₂ are O; Q is O; W is P; and R^(A), R⁸, R¹⁵, R¹⁶,R₁₀₃, R₁₀₄, R₁₀₅, M, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(c),and the substituents of R^(3a), R^(7a) and R⁶ are as defined in formula(II).

For example, the present invention provides a compound of formula (II)wherein R⁴ is OR¹⁶; R⁵ is H; R² is C1, C2, C3, C4 or C5 alkyl; R³ isphenylmethyl wherein the phenyl moiety of the phenylmethyl isunsubstituted or substituted with one R^(3a); R^(3a) is unsubstituted orsubstituted pyridyl; R⁶ is unsubstituted or substituted phenylmethyl; R⁷is —N(R_(b))C(O)OR_(a), C1-C5 alkyl or tetrahydrofuranyl wherein theC1-C5 alky is substituted with 0, 1 or 2 substituents selected from thegroup consisting of halo, —OR_(a), —OC(O)R_(a), —SR_(a), —SOR_(a),—SO₂R_(a), —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))C(O)OR_(a),—N(R_(a))C(═N)NR_(a)R_(b), —N(R_(a))C(O)NR_(a)R_(b), —C(O)NR_(a)R_(b),—C(O)OR_(a) and R^(7a), wherein R_(a) and R_(b) are independentlyselected from the group consisting of hydrogen and C1-C5 alkyl andR^(7a) is unsubstituted or substituted pyridyl or unsubstituted orsubstituted thiazolyl; R¹ is C1-C5 alkyl; Z₁ and Z₂ are O; Q is O; W isP; and R^(A), R⁸, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, M′, R₁₀₆, R₁₀₇, R₁₀₈,q, m, m′, m″, r, t, R_(c) and the substituents of R^(3a), R⁶ are asdefined in formula (II).

For example, the present invention provides a compound of formula (II)wherein R⁴ is H; R⁵ is OR¹⁶; R² is C1, C2, C3, C4 or C5 alkyl; R³ isphenylmethyl wherein the phenyl moiety of the phenylmethyl isunsubstituted or substituted with one R^(3a); R^(3a) is unsubstituted orsubstituted pyridyl; R⁶ is unsubstituted or substituted phenylmethyl; R⁷is —N(R_(b))C(O)OR_(a), C1-C5 alkyl or tetrahydrofuranyl wherein each ofthe C1-C5 alky is independently substituted with 0, 1 or 2 substituentselected from the group consisting of halo, —OR_(a), —OC(O)R_(a),—SR_(a), —SOR_(a), —SO₂R_(a), —NR_(a)R_(b), —N(R_(b))C(O)R_(a),—N(R_(b))C(O)OR_(a), —N(R_(a))C(═N)NR_(a)R_(b),—N(R_(a))C(O)NR_(a)R_(b), —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(7a),wherein R_(a) and R_(b) are independently selected from the groupconsisting of hydrogen and C1-C5 alkyl and R^(7a) is unsubstituted orsubstituted pyridyl or unsubstituted or substituted thiazolyl; R¹ isC1-C5 alkyl; Z₁ and Z₂ are O; Q is O; W is P; R₁₀₄ is hydrogen or C1-C5alkyl; each M is independently selected from the group consisting ofhydrogen and C1-C5 alkyl; and R^(A), R⁸, R¹⁵, R¹⁶, R₁₀₃, R₁₀₅, M′, R₁₀₆,R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(c) and the substituents of R^(3a),R^(7a), M and R⁶ are as defined in formula (II).

For example, the present invention provides a compound of formula (II)wherein R⁴ is OR¹⁶; R⁵ is H; R² is C1, C2, C3, C4 or C5 alkyl; R³ isphenylmethyl wherein the phenyl moiety of the phenylmethyl isunsubstituted or substituted with one R^(3a); R^(3a) is unsubstituted orsubstituted pyridyl; R⁶ is unsubstituted or substituted phenylmethyl; R⁷is —N(R_(b))C(O)OR_(a), C1-C5 alkyl or tetrahydrofuranyl wherein each ofthe C1-C5 alky is independently substituted with 0, 1 or 2 substituentsselected from the group consisting of halo, —OR_(a), —OC(O)R_(a),—SR_(a), —SOR_(a), —SO₂R_(a), —NR_(a)R_(b), —N(R_(b))C(O)R_(a),—N(R_(b))C(O)OR_(a), —N(R_(a))C(═N)NR_(a)R_(b),—N(R_(a))C(O)NR_(a)R_(b), —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(7a),wherein R_(a) and R_(b) are independently selected from the groupconsisting of hydrogen and C1-C5 alkyl and R^(7a) is unsubstituted orsubstituted pyridyl or unsubstituted or substituted thiazolyl; R¹ isC1-C5 alkyl; Z₁ and Z₂ are O; Q is O; W is P; R₁₀₄ is hydrogen or C1-C5alkyl; each M is independently selected from the group consisting ofhydrogen, and C1-C5 alkyl; and R^(A), R⁸, R¹⁵, R¹⁶, R₁₀₃, R₁₀₅, R₁₀₇,R₁₀₈, M′, R₁₀₆, q, m, m′, m″, r, t, R_(c) and the substituents ofR^(3a), M, R^(7a) and R⁶ are as defined in formula (II).

For example, the present invention provides a compound of formula (II)wherein R⁴ is H; R⁵ is OR¹⁶; R² is 1-methylpropyl, tert-butyl orisopropyl; R³ is phenylmethyl wherein the phenyl moiety of thephenylmethyl is unsubstituted or substituted with one R^(3a); R^(3a) isunsubstituted or substituted pyridyl; R⁶ is unsubstituted or substitutedphenylmethyl; R⁷ is —N(H)C(O)OCH₃, methyl, ethyl, propyl, r-butyl,1-methylpropyl, 2-methylpropyl, 3-methylpropyl, tert-butyl, isopropyl,or tetrahydrofuranyl wherein each of the methyl, ethyl, propyl, r-butyl,1-methylpropyl, 2-methylpropyl, 3-methylpropyl, tert-butyl, isopropyl isindependently substituted with 0, 1 or 2 substituents selected from thegroup consisting of halo, —OR_(a), —OC(O)R_(a), —SR_(a), —SOR_(A),—SO₂R_(a), −NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))C(O)OR_(a),—N(R_(a))C(═N)NR_(a)R_(b), —N(R_(a))C(O)NR_(a)R_(b), —C(O)NR_(a)R_(b),—C(O)OR_(a) and R^(7a), wherein R_(a) and R_(b) are independentlyselected from the group consisting of hydrogen and C1-C5 alkyl andR^(7a) is unsubstituted or substituted pyridyl or unsubstituted orsubstituted thiazolyl; R¹ is C1-C5 alkyl; Z₁ and Z₂ are O; Q is O; W isP; R₁₀₄ is hydrogen or C1-C5 alkyl; each M is independently selectedfrom the group consisting of hydrogen and C1-C5 alkyl; and R^(A), R⁸,R¹⁵, R¹⁶, R₁₀₃, R₁₀₅, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(c)and the substituents of R^(3a), R^(7a), M and R⁶ are as defined informula (II).

For example, the present invention provides a compound of formula (II)wherein R⁴ is OR¹⁶; R⁵ is H; R² is 1-methylpropyl, tert-butyl orisopropyl; R³ is phenylmethyl wherein the phenyl moiety of thephenylmethyl is unsubstituted or substituted with one R^(3a); R^(3a) isunsubstituted or substituted pyridyl; R⁶ is unsubstituted or substitutedphenylmethyl; R⁷ is —N(H)C(O)OCH₃, methyl, ethyl, propyl, n-butyl,1-methylpropyl, 2-methylpropyl, 3-methylpropyl, tert-butyl, isopropyl,or tetrahydrofuranyl wherein each of the methyl, ethyl, propyl, n-butyl,1-methylpropyl, 2-methylpropyl, 3-methylpropyl, tert-butyl and isopropylis substituted with 0, 1 or 2 substituents selected from the groupconsisting of halo, —OR_(a), —OC(O)R_(a), —SR_(a), —SOR_(a), —SO₂R_(a),—NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))C(O)OR_(a),—N(R_(a))C(═N)NR_(a)R_(b) , —N(R_(a))C(O)NR_(a)R_(b), —C(O)NR_(a)R_(b),—C(O)OR_(a) and R^(7a), wherein R_(a) and R_(b) are independentlyselected from the group consisting of hydrogen and C1-C5 alkyl andR^(7a) is unsubstituted or substituted pyridyl or unsubstituted orsubstituted thiazolyl; R¹ is C1-C5 alkyl; Z₁ and Z₂ are O; Q is O; W isP; R₁₀₄ is hydrogen or C1-C5 alkyl; each M is independently selectedfrom the group consisting of hydrogen, and C1-C5 alkyl; and R^(A), R⁸,R¹⁵, R¹⁶, R₁₀₃, R₁₀₅, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m|, r, t, R_(c)and the substituents of R^(3a), R^(7a), M and R⁶ are as defined informula (II).

Exemplary compounds of the present invention of formula (II) include,but not limited, to the following:

methyl(1S,4R,6S,7S,10S)-7-benzyl-1,10-ditert-butyl-6-hydroxy-2,9,12-trioxo-4-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1S,4S,5S,7S,10S)-7-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-4-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1R,4S,5S,7S,10S)-4-benzyl-10-tert-butyl-5-hydroxy-1-[1-methyl-1-(methylsulfanyl)ethyl]-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1R,4S,5S,7S,10S)-4-benzyl-10-tert-butyl-5-hydroxy-1-[1-methyl-1-(methylsulfanyl)ethyl]-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1R,4S,6S,7S,10S)-4-benzyl-10-tert-butyl-6-hydroxy-1-[1-methyl-1-(methylsulfanyl)ethyl]-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1R,4S,6S,7S,10S)-4-benzyl-10-tert-butyl-6-hydroxy-1-[1-methyl-1-(methylsulfonyl)ethyl]-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1S)-1-[({(1S,3S,4S)-4-({(2S)-3,3-dimethyl-2-[(phenoxyacetyl)amino]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S,4S,6S,7S,10S)-7-benzyl-1,10-ditert-butyl-6-hydroxy-2,9,12-trioxo-4-[4-(2-pyridinyl)benzyl]-14-oxa-3,8,11-triazapentadec-1-ylcarbamate;

methyl(1S)-1-[({(1S,3S,4S)-4-{[(2S)-3,3-dimethyl-2-({[(6-methyl-3pyridinyl)oxy]acetyl}amino)butanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

3-pyridinylmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

benzyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1S,4S,5S,7S,10S)-7-benzyl-1,10-ditert-butyl-5-hydroxy-4-[4-(6-methyl-3-pyridinyl)benzyl]-2,9,12-trioxo-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1S,4S,5S,7S,10S)-7-benzyl-1,10-ditert-butyl-5-hydroxy-4-[4-(5-methylpyridinyl)benzyl]-2,9,12-trioxo-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-ditert-butyl-5-hydroxy-7-[4-(5-methyl-2-pyridinyl)benzyl]-2,9,12-trioxo-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1R,4S,5S,7S,10S)-4-benzyl-10-tert-butyl-5-hydroxy-1-[1-methyl-1-((R)-methylsulfonyl)ethyl]-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1R,4S,5S,7S,10S)-4-benzyl-10-tert-butyl-5-hydroxy-1-[1-methyl-1-((S)-methylsulfinyl)ethyl]-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1S,4S,5S,7S,10S)-7-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-4-[4-(3-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1S,4S,5S,7S,10S)-7-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-4-[4-(3-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

1,2,5,6-tetradeoxy-2,5-bis({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-1,6-bis[4-(2-pyridinyl)phenyl]-D-iditol;

methyl(1S,4R,5R,7R,10S)-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-4,7-bis[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1S,4S,5S,7S,10S)-7-benzyl-1,10-ditert-butyl-5-hydroxy-4-[4-(6-methoxy-2-pyridinyl)benzyl]-2,9,12-trioxo-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-ditert-butyl-5-hydroxy-7-[4-(6-methoxy-2-pyridinyl)benzyl]-2,9,12-trioxo-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-disec-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1S,4S,5S,7S,10S)-4-benzyl-10-tert-butyl-5-hydroxy-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-1-[(3R)-tetrahydrofuran-3-yl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-di-tert-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(1,3-thiazol-2-yl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1S,4S,5S,7S,10S)-4-benzyl-10-tert-butyl-5-hydroxy-1-[(1S)-1-methylpropyl]-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-di-tert-butyl-5-hydroxy-2,9,12-trioxo-7-(4-pyridin-3-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1S)-1-({[(1S,3S,4S)-3-hydroxy-4-{[(2S)-2-methyl-3-(methylsulfonyl)propanoyl]amino}-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S,4S,5S,7S,10S)-4benzyl-1,10-di-tert-butyl-5-hydroxy-2,9,12-trioxo-7-(4-pyridin-4-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1S)-1-({[(1S,3S,4S)-3-hydroxy-4-{[(2S)-2-hydroxy-3,3-dimethylbutanoyl]amino}-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S,4S,6S,7S,10S)-7-benzyl-1,10-di-tert-butyl-6-hydroxy-12,12-dioxido-2,9-dioxo-4-(4-pyridin-2-ylbenzyl)-12-thia-3,8,11-triazatridec-1-ylcarbamate;

methyl(1R,4S,5S,7S,10S)-4-benzyl10-tert-butyl-5-hydroxy-1-[(methylthio)methyl]-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8, 11-triazatetradec-1-ylcarbamate;

methyl(1R,4S,5S,7S,10S)-4-benzyl10-tert-butyl-5-hydroxy-1-[(methylsulfonyl)methyl]-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8, 11-triazatetradec-1-ylcarbamate;

methyl(1S)-1-({[(1S,3S,4S)-3-hydroxy-4-{[(2R)-2-hydroxy-3-methyl-3-(methylsulfonyl)butanoyl]amino}-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S,4S,5S,7S,10S)-4benzyl-10-tert-butyl-5-hydroxy-1-isobutyl-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1S,4S,5S,7S,10S)-1-(2-amino-2-oxoethyl)-4-benzyl-10-tert-butyl-5-hydroxy-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl2-{[(1S,2S,4S)-1-benzyl-2-hydroxy-4-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-5-(4-pyridin-2-ylphenyl)pentyl]amino}-1-[(methoxycarbonyl)amino]-2-oxoethylcarbamate;

methyl(1S,4S,6S,7S,10S)-7-benzyl-1,10-di-tert-butyl-6-hydroxy-2,9,12,14tetraoxo-4-(4-pyridin-2-ylbenzyl)-15-oxa-3,8,11,13-tetraazahexadec-1-ylcarbamate;

methyl(1S,4S,6S,7S,10S)-7-benzyl-1,10-di-tert-butyl-6-hydroxy-14,14dimethyl-2,9,12,15-tetraoxo-4-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazahexadec-1-ylcarbamate;

(4S,7S,8S,10S,13S)-7-benzyl-4,13-di-tert-butyl-8-hydroxy-2,5,12,15-tetraoxo-10-(4-pyridin-2-ylbenzyl)-16-oxa-3,6,11,14-tetraazaheptadec-1-ylacetate;

methyl(1S)-1-({[(1S,3S,4S)-4-{[(2S)-2-(glycoloylamino)-3,3-dimethylbutanoyl]amino}-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

(3S,6S,7S,9S,12S)-6-benzyl-3-[(tert-butoxycarbonyl)amino]-12-tert-butyl-7-hydroxy-2,2-dimethyl-4,11,14-trioxo-9-(4-pyridin-2-ylbenzyl)-15-oxa-5,10,13-triazahexadec-1-ylacetate;

methyl(1S,4S,5S,7S,10S)-4benzyl-10-tert-butyl-5-hydroxy-1-(2-hydroxy-1,1-dimethylethyl)-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1S,4S,5S,7S,10S)-1-{[(aminocarbonyl)amino]methyl}-4-benzyl-10-tert-butyl-5-hydroxy-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1S,4S,5S,7S,10S)-4benzyl-10-tert-butyl-5-hydroxy-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-1-(pyridin-2-ylmethyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1S,4S,5S,7S,10S)-4benzyl-10-tert-butyl-5-hydroxy-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-1-(1,3-thiazol-4-ylmethyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

(3S,6S,7S,9S,12S)-6-benzyl12-tert-butyl-7-hydroxy-3-[(methoxycarbonyl)amino]-2,2-dimethyl-4,11,14-trioxo-9-(4-pyridin-2-ylbenzyl)-15-oxa-5,10,13-triazahexadec-1-ylacetate;

methyl(1S,4R,6S,7S,10S)-7-benzyl1,10-di-tert-butyl-6-hydroxy-15,15-dioxido-2,9-dioxo-4-(4-pyridin-2-ylbenzyl)-15-thia-3,8,11,14tetraazahexadec-1-ylcarbamate;

methyl(1S,4R,6S,7S,10S)-7-benzyl1,10-di-tert-butyl-6-hydroxy-2,9,15-trioxo-4-(4-pyridin-2-ylbenzyl)-16-oxa-3,8,11,14-tetraazaheptadec-1-ylcarbamate;

methyl(5S,8S,10S,11S,14S)-10-benzyl-5-tert-butyl-10-hydroxy-14-[(methoxycarbonyl)amino]-15-methyl-3,6,13-trioxo-8-(4-pyridin-2-ylbenzyl)-2-oxa-4,7,12-triazahexadecan-16-oate;

methyl(5S,8S,10S,11S,14S)-11-benzyl-5-tert-butyl-10-hydroxy-14-[(methoxycarbonyl)amino]-15,15-dimethyl-3,6,13-trioxo-8-(4-pyridin-2-ylbenzyl)-2-oxa-4,7,12-triazahexadecan-16-oate;

methyl(1S,4S,5S,7S,10S)-4benzyl-1,10-bis(tert-butyl)-2,9,12-trioxo-5-(phosphonooxy)-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1S,4S,5S,7S,10S)-7-benzyl-1,10-bis(tert-butyl)-2,9,12-trioxo-5-[(phosphonooxy)methoxy]-4-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-bis(tert-butyl)-2,9,12-trioxo-5-[(phosphonooxy)methoxy]-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;

methyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-bis(tert-butyl)-2,9,12-trioxo-5-[1-(phosphonooxy)ethoxy]-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;and

methyl(1S)-3-amino-1-({[(1S,2S,4S)-1-benzyl-2-hydroxy-4-{[N-methoxycarbonyl)-3-methyl-L-valyl]amino}-5-(4-pyridin-2-ylphenyl)pentyl]amino}carbonyl)-2,2-dimethyl-3-oxopropylcarbamate;or a pharmaceutical acceptable salt form, prodrug, or stereoisomerthereof.

In a third embodiment, the present invention provides a compound offormula (III)

or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, wherein:

-   B is H or —CH₂R^(9;)-   L is —C(═(O), —C(═S), —C(═NH) or —S(O)₂;-   R¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,    heterocycle, aryl or heteroaryl; wherein each R¹ is substituted with    0, 1 or 2 substituents independently selected from the group    consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl,    hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),    —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂, and    R^(1a);-   R^(1a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(1a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R² is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,    heterocycle, aryl or heteroaryl; wherein each R² is substituted with    0, 1 or 2 substituents independently selected from the group    consisting of halo, —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a),    NR_(a)R_(b), NR_(b)C(O)R_(a) —N(R_(a))C(O)OR_(a),    —N(R_(a))C(═N)NR_(a)R_(b), —N(R_(a))C(O)NR_(a)R_(b),    —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(2a);-   R^(2a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(2a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R³ is alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, -alkylOR_(a),    -alkylSR_(a), -alkylSOR_(a), -alkylSO₂R_(a), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)OR_(a),    -alkylN(R_(a))C(═N)NR_(a)R_(b), -alkylN(R_(a))C(O)NR_(a)R_(b),    -alkylC(O)NR_(a)R_(b), -alkylC(O)OR_(a), cycloalkyl,    cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle,    heterocyclealkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;    wherein the cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl,    cycloalkyl moiety of the cycloalkylalkyl, cycloalkenyl moiety of the    cycloalkenylalkyl, heterocycle moiety of the heterocyclealkyl,    heteroaryl moiety of the heteroarylalkyl and the aryl moiety of the    arylalkyl are independently substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and    R^(3a);-   R^(3a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(3a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    oxo, alkyl, alkenyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), and -alkylC(O)N(alkyl)₂;-   R⁴ is H and R⁵ is OR¹⁶; or-   R⁵ is H and R⁴ is OR¹⁶; or-   R⁴ and R⁵ are —OR¹⁶;-   R⁶ is alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, -alkylOR_(a),    -alkylSR_(a), -alkylSOR_(a), -alkylSO₂R_(a), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)OR_(a), -alkylN(R_(a)    )C(═N)NR_(a)R_(b), -alkylN(R_(a))C(O)NR_(a)R_(b),    -alkylC(O)NR_(a)R_(b), -alkylC(O)OR_(a), cycloalkyl,    cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle,    heterocyclealkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;    wherein the cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl,    cycloalkyl moiety of the cycloalkylalkyl, cycloalkenyl moiety of the    cycloalkenylalkyl, heterocycle moiety of the heterocyclealkyl,    heteroaryl moiety of the heteroarylalkyl and the aryl moiety of the    arylalkyl are independently substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and    R^(6a);-   R^(6a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(6a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    oxo, alkyl, alkenyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), and -alkylC(O)N(alkyl)₂;-   R⁷ is —N(R_(b))C(O)OR_(a), alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, heterocycle, aryl or heteroaryl; wherein the alkyl,    alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl and    heteroaryl are independently substituted with 0, 1 or 2 substituents    independently selected from the group consisting of halo, —OR_(a),    —OC(O)R_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —NR_(a)R_(b),    —N(R_(b))C(O)R_(a), —N(R_(b))C(O)OR_(a), —N(R_(a))C(═N)NR_(a)R_(b),    —N(R_(a))C(O)NR_(a)R_(b), —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(7a);-   R^(7a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(7a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R⁹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R⁹ is substituted with 0, 1,    2 or 3 substituents independently selected from the group consisting    of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro, oxo,    —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))SO₂R_(a),    —N(R_(b))SO₂NR_(a)R_(b), —N(R_(b))C(O)NR_(a)R_(b),    —N(R_(b))C(O)OR_(a), —C(O)R_(a), —C(O)NR_(a)R_(b), —C(O)OR_(a),    haloalkyl, nitroalkyl, cynaoalkyl, formylalkyl, -alkylOR_(a),    -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)OR_(a), -alkylN(R_(b))SO₂NR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkylC(O)R_(a),    -alkylC(O)NR_(a)R_(b) and R^(9a);-   R^(9a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(9a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹⁶ is hydrogen or R¹⁵;-   R¹⁵ is

-   R₁₀₃ is C(R₁₀₅)₂, O or —N(R₁₀₅);-   R₁₀₄ is hydrogen, alkyl, haloalkyl, alkoxycarbonyl, aminocarbonyl,    alkylaminocarbonyl or dialkylaminocarbonyl,-   each M is independently selected from the group consisting of H,    —N(R₁₀₅)₂, alkyl, alkenyl, and R₁₀₆; wherein 1 to 4 —C₂ radicals of    the alkyl or alkenyl, other than the —CH₂ radical that is bound to    Z, is optionally replaced by a heteroatom group selected from the    group consisting of O, S, S(O), SO₂ and N(R₁₀₅); and wherein any    hydrogen in said alkyl, alkenyl or R₁₀₆ is optionally replaced with    a substituent selected from the group consisting of oxo, —OR₁₀₅,    —R₁₀₅, —N(R₁₀₅)₂, —CN, —C(O)OR₁₀₅, —C(O)N(R₁₀₅)₂, —SO₂N(R₁₀₅),    —N(R₁₀₅)C(O)R₁₀₅, —C(O)R₁₀₅, —SR₁₀₅, —S(O)R₁₀₅, —SO₂R₁₀₅, —OCF₃,    —SR₁₀₆, —SOR₁₀₆, —SO₂R₁₀₆, —N(R₁₀₅)SO₂R₁₀₅, halo, —CF₃, NO₂ and    phenyl; provided that when M is —N(R₁₀₅)₂, Z₁ and Z₂ are —CH₂;-   Z₁ is CH₂, O, S, N(R₁₀₅), or, when M is absent, H;-   Z₂ is CH₂, O, S or —N(R₁₀₅);-   Q is O or S;-   W is P or S; wherein when W is S, Z₁ and Z₂ are not S;-   M′ is H, alkyl, alkenyl or R₁₀₆; wherein 1 to 4—CH₂ radicals of the    alkyl or alkenyl is optionally replaced by a heteroatom group    selected from O, S, S(O), SO₂ or N(R₁₀₅); and wherein any hydrogen    in said alkyl, alkenyl or R₁₀₆ is optionally replaced with a    substituent selected from the group consisting of oxo, —OR₁₀₅,    —R₁₀₅, —N(R₁₀₅)₂, —CN, —C(O)OR₁₀₅, —C(O)N(R₁₀₅)₂, —SO₂N(R₁₀₅),    —N(R₁₀₅)C(O)R₁₀₅, —C(O)R₁₀₅, —SR₁₀₅, —S(O)R₁₀₅, —SO₂R₁₀₅, —OCF₃,    —SR₁₀₆, —SOR₁₀₆, —SO₂R₁₀₆, —N(R₁₀₅)SO₂R₁₀₅, halo, —CF₃ and NO₂;-   R₁₀₆ is a monocyclic or bicyclic ring system selected from the group    consisting of aryl, cycloalkyl, cycloalkenyl heteroaryl and    heterocycle; wherein any of said heteroaryl and heterocycle ring    systems contains one or more heteroatoms selected from the group    consisting of O, N, S, SO, SO₂ and N(R₁₀₅); and wherein any of said    ring system is substituted with 0, 1, 2, 3, 4, 5 or 6 substituents    selected from the group consisting of hydroxy, alkyl, alkoxy, and    —OC(O)alkyl;-   each R₁₀₅ is independently selected from the group consisting of H    or alkyl; wherein said alkyl is optionally substituted with a ring    system selected from the group consisting of aryl, cycloalkyl,    cycloalkenyl, heteroaryl and heterocycle; wherein any of said    heteroaryl and heterocycle ring systems contains one or more    heteroatoms selected from the group consisting of O, N, S, SO, SO₂,    and N(R₁₀₅); and wherein any one of said ring systems is substituted    with 0, 1, 2, 3 or 4 substituents selected from the group consisting    of oxo, —OR₁₀₅, —R₁₀₅, —N(R₁₀₅)₂, —N(R₁₀₅)C(O)R₁₀₅, —CN, —C(O)OR₁₀₅,    —C(O)N(R₁₀₅)₂, halo and —CF₃;-   each R₁₀₇ and R₁₀₈ are independently selected from the group    consisting of hydrogen and alkyl;-   q is 0 or 1;-   m is 0 or 1;-   m′ is 0 or 1;-   m″ is 0 or 1;-   r is 0, 1, 2, 3 or 4;-   t is 0 or 1;-   R_(a) and R_(b) at each occurrence are independently selected from    the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    cycloalkyl, aryl, heteroaryl and heterocycle; wherein each R_(a) and    R_(b), at each occurrence, is independently substituted with 0, 1, 2    or 3 substituents independently selected from the group consisting    of cyano, nitro, halo, oxo, hydroxy, alkoxy, alkyl, alkenyl,    alkynyl, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),    —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and R_(c);    alternatively, R_(a) and R_(b), together with the nitrogen atom to    which they are attached, form a ring selected from the group    consisting of heteroaryl and heterocycle; wherein each of the    heteroaryl and heterocycle is independently substituted with 0, 1, 2    or 3 substituents independently selected from the group consisting    of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo,    hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),    —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, formylalkyl,    nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH₂,    -alkylN(H)(alkyl), -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂,    -alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH,    -alkylC(O)Oalkyl, -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl),    -alkylC(O)N(alkyl)₂ and R_(c);-   R_(c) is aryl, heteroaryl or heterocycle; wherein each R_(c) is    independently substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of halo, nitro,    oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkyl-NH₂, -alkyl-N(H)(alkyl), -alkyl-N(alkyl)₂,    -alkyl-N(H)C(O)NH₂, -alkyl-N(H)C(O)N(H)(alkyl),    -alkyl-N(H)C(O)N(alkyl)₂, -alkyl-C(O)OH, -alkyl-C(O)Oalkyl,    -alkyl-C(O)NH₂, -alkyl-C(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂; and    n is 1 or 2.

For example, the present invention provides a compound of formula (III)wherein R⁴ is H; R⁵ is OR¹⁶; and L, B, R¹, R^(1a), R², R_(2a), R³,R^(3a), R⁶, R^(6a), R⁷, R^(7a), R⁹, R^(9a), R¹⁵, R¹⁶, R¹⁵, R₁₀₃, R₁₀₄,R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m′, m′, m″, r, t, R_(a),R_(b), R_(c) and n are as defined in formula (III).

For example, the present invention provides a compound of formula (III)wherein R⁴ is OR¹⁶; R⁵ is H; and L, B, R¹, R^(1a), R², R^(2a), R³,R^(3a), R⁶, R^(6a), R⁷, R^(7a), R⁹, R^(9a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅,M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b),R_(c) and n are as defined in formula (III).

For example, the present invention provides a compound of formula (III)wherein R¹ is a l; and L, B, R², R^(2a), R³, R^(3a), R⁴, R⁵, R⁶, R^(6a),R⁷, R^(7a), R⁹, R^(9a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′,R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m′, r, t, R_(a), R_(b), R_(c) and n are asdefined in formula (III).

For example, the present invention provides a compound of formula (III)wherein R¹ is methyl; and L, B, R², R^(2a), R³, R^(3a), R⁴, R⁵, R⁶,R^(6a), R⁷, R^(7a), R⁹, R^(9a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂,Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c) andn are as defined in formula (III).

For example, the present invention provides a compound of formula (III)wherein R² is alkyl; and L, B, R¹, R^(1a), R³, R^(3a), R⁴, R⁵, R⁶,R^(6a), R⁷, R^(7a), R⁹, R^(9a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂,Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m′, r, t, R_(a), R_(b), R_(c) andn are as defined in formula (III).

For example, the present invention provides a compound of formula (III)wherein R² is tert-butyl, 1-methylpropyl or isopropyl; and L, B, R¹,R_(1a), R³, R^(3a), R⁴, R⁵, R⁶, R^(6a), R⁷, R^(7a), R⁹, R^(9a), R¹⁵,R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′,m″, r, t, R_(a), R_(b), R_(c) and n are as defined in formula (III).

For example, the present invention provides a compound of formula (III)wherein R³ is arylalkyl wherein the aryl moiety of the arylalkyl issubstituted with 0, 1, 2, 3 or 4 substituents independently selectedfrom the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl,alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH,—S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl,—N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH,—C(O)Oalkyl, —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl,hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),-alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),-alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl, -alkylC(O)NH₂,-alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and R^(3a); and L, B, R¹,R^(1a), R², R^(2a), R^(3a), R⁴, R⁵, R⁶, R^(6a), R⁷, R^(7a), R⁹, R^(9a),R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m,m′, m″, r, t, R_(a), R_(b), R_(c) and n are as defined in formula (III).

For example, the present invention provides a compound of formula (III)wherein R³ is phenylmethyl, wherein the phenyl moiety of thephenylmethyl is unsubstituted or substituted with 0, 1, 2, 3 or 4substituents selected from the group consisting of cyano, halo, nitro,oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),—N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,—N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),—N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂, —C(O)N(H)(alkyl),—C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH₂,alkylN(H)(alkyl), -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂,-alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH,-alkylC(O)Oalkyl, -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl),-alkylC(O)N(alkyl)₂ and R^(3a); and L, B, R¹, R^(1a), R², R^(2a),R^(3a), R⁴, R⁵, R⁶, R^(6a), R⁷, R^(7a), R⁹, R^(9a), R¹⁵, R¹⁶, R₁₀₃,R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t,R_(a), R_(b), R_(c) and n are as defined in formula (III).

For example, the present invention provides a compound of formula (III)wherein R⁶ is unsubstituted or substituted arylalkyl; and L, B, R¹,R^(1a), R², R^(2a), R³, R^(3a), R₄, R⁵, R⁷, R^(7a), R⁹, R^(9a), R¹⁵,R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′,m″, r, t, R_(a), R_(b), R_(c), n and the substituents of R⁶ are asdefined in formula (III).

For example, the present invention provides a compound of formula (III)wherein R⁶ is unsubstituted or substituted phenylmethyl; and L, B, R¹,R^(1a), R², R^(2a), R³, R³, R⁴, R⁵, R⁷, R^(7a), R₉, R^(9a), R⁵, R¹⁶,R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″,r, t, R_(a), R_(b), R_(c), n and the substituents of R⁶ are as definedin formula (III).

For example, the present invention provides a compound of formula (III)wherein R⁷ is —N(R_(b))C(O)OR_(a), alkyl or heterocycle wherein thealkyl and heterocycle are independently substituted with 0, 1 or 2substituents independently selected from the group consisting of halo,—OR_(a), —OC(O)R_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —NR_(a)R_(b),—N(R_(b))C(O)R_(a), —N(R_(b))C(O)OR_(a), —N(R_(a))C(═N)NR_(a)R_(b),—N(R_(a))C(O)NR_(a)R_(b), —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(7a);; andL, B, R¹, R^(1a), R², R^(2a), R³, R^(3a), R⁴, R⁵, R⁶, R^(6a), R^(7a),R⁹, R^(9a), R¹⁵, R⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇,R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c) and n are as defined informula (III).

For example, the present invention provides a compound of formula (III)wherein R⁷ is —N(H)C(O)OCH₃, methyl, ethyl, n-propyl, n-butyl, n-pentyl,tert-butyl, isopropyl, 1-methypropyl, 2-methylpropyl, 3-methylpropyl ortetrahydrofuranyl, wherein each of the methyl, ethyl, n-propyl, n-butyl,n-pentyl, tert-butyl, isopropyl, 1-methypropyl, 2-methylpropyl,3-methylpropyl is independently substituted with 0, 1 or 2 substituentsindependently selected from the group consisting of halo, —OR_(a),—OC(O)R_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —NR_(a)R_(b),—N(R_(b))C(O)R_(a), —N(R_(b))C(O)OR_(a), —N(R_(a))C(═N)NR_(a)R_(b),—N(R_(a))C(O)NR_(a)R_(b), —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(7a),wherein R_(a) and R_(b) are each independently selected from the groupconsisting of hydrogen, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl and C5alkyl and R^(7a) is substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl; and L, B, R¹, R^(1a), R², R^(2a), R³, R^(3a),R⁴, R⁵, R⁶, R^(6a), R⁹, R^(9a), R¹⁵, R¹⁶, R₁₀₃ , R₁₀₄, R₁₀₅, M, Z₁, Z₂,Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c) nand the substituents of R^(7a) are as defined in formula (III).

For example, the present invention provides a compound of formula (III)wherein R⁹is aryl or heteroaryl, wherein each R⁹ is substituted with 0,1, 2 or 3 substituents independently selected from the group consistingof alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro, oxo, —OR_(a),—SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a), —NR_(a)R_(b),—N(R_(b))C(O)R_(a), —N(R_(b))SO₂R_(a), —N(R_(b))SO₂NR_(a)R_(b),—N(R_(b))C(O)NR_(a)R_(b), —N(R_(b))C(O)OR_(a), —C(O)R_(a),—C(O)NR_(a)R_(b), —C(O)OR_(a), —C(O)R_(a), —C(O)NR_(a)R_(b),—C(O)OR_(a), haloalkyl, nitroalkyl, cynaoalkyl, formylalkyl,-alkylOR_(a), -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),-alkylN(R_(b))C(O)OR_(a), -alkylN(R_(b))SO₂NR_(a)R_(b),-alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),-alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkylC(O)R_(a),-alkylC(O)NR_(a)R_(b) and R^(9a), wherein R_(a) and R_(b)are eachindependently selected from the group consisting of hydrogen, C1alkyl,C2 alkyl, C3 alkyl, C4 alkyl and C5 alkyl; and L, B, R¹, R^(1a), R²,R^(2a), R³, R^(3a), R⁴, R⁵, R⁶, R^(6a), R⁷, R^(7a), R^(9a), R¹⁵, R¹⁶,R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″,r, t, R_(a), R_(b), R_(c) and n are as defined in formula (III).

For example, the present invention provides a compound of formula (III)wherein R⁹is phenyl substituted with 0, 1, 2 or 3 substituentsindependently selected from the group consisting of C1 alkyl, C2 alky,C3 alkyl, C4 alkyl, C5 alkyl, halo, —OR_(a), —SR_(a), —SOR_(a),—SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a), —NR_(a)R_(b), —N(R_(b))C(O)R_(a),—N(R_(b))SO₂R_(a), —N(R_(b))SO₂NR_(a)R_(b), —N(R_(b))C(O)NR_(a)R_(b),—N(R_(b)C(O)OR) _(a), —C(O)R_(a), —C(O)NR_(a)R_(b), —C(O)OR_(a),haloalkyl, -alkylOR_(a), -alkyl-O—P(O)(OR_(a))(OR_(a)) and R^(9a),wherein R_(a) and R_(b) are each selected from the group consisting ofhydrogen, methyl, C1 alkyl, C2 alky, C3 alkyl, C4 alkyl, and C5 alkyland R^(9a) is pyridyl; and L, B, R¹, R^(1a), R², W, R¹, R^(1a), R⁴, R⁵,R⁶, R^(6a), R⁷, R^(7a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′,R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c) and n are asdefined in formula (III).

For example, the present invention provides a compound of formula (III)wherein R⁹ is heteroaryl; wherein each R⁹ is substituted with 0, 1, 2 or3 substituents independently selected from the group consisting ofalkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro, oxo, —OR_(a),—SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a), —NR_(a)R_(b),—N(R_(b))C(O)R_(a), —N(R_(b))SO₂R_(, —N(R) _(b))SO₂NR_(a)R_(b),—N(R_(b))C(O)NR_(a)R_(b), —N(R_(b)C(O)OR) _(a), —C(O)R_(a),—C(O)NR_(a)R_(b), —C(O)OR_(a), haloalkyl, nitroalkyl, cynaoalkyl,formylalkyl, -alkylOR_(a), -alkyl-O—P(O)(OR_(a))(OR_(a)),-alkylNR_(a)R_(b), -alkylN(R_(b))C(O)OR_(a),-alkylN(R_(b))SO₂NR_(a)R_(b), -alkylN(R_(b))C(O)R_(a),-alkylN(R_(b)C(O)NR) _(a)R_(b), -alkylN(R_(b))SO₂R_(a),-alkylC(O)OR_(a), -alkylC(O)R_(a), -alkylC(O)NR_(a)R_(b) and R^(9a),wherein R_(a) and R_(b) are each independently selected from the groupconsisting of hydrogen, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl and C5alkyl, and R^(9a) is substituted or substituted heteroaryl; and L, B,R¹, R^(1a), R², R^(2a), R³, R^(3a), R⁴, R⁵, R⁶, R⁷, R^(7a), R¹⁵, R¹⁶,R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″,r, t, R_(a), R_(b), R_(c) n and the substituents of R^(9a) are asdefined in formula (III).

For example, the present invention provides a compound of formula (III)wherein R⁹is thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl,imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, isoquinolinyl,quinolinyl, pyridyl, phenyl, imidazo[1,5,a]pyridyl, benzimiazolyl,benzothienyl, benzthiazolyl or indazolyl, wherein each R⁹ isindependently substituted with 0, 1, 2 or 3 substituents independentlyselected from the group consisting of alkyl, alkenyl, alkynyl, cyano,formyl, halo, nitro, oxo, —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a),—SO₂NR_(a), —SO₂OR_(a), —NR_(a)R_(b), —N(R_(b))C(O)R_(a),—N(R_(b))SO₂R_(a), —N(R_(b))SO₂NR_(a)R_(b), —N(R_(b))C(O)NR_(a)R_(b),—N(R_(b))C(O)OR_(a), —C(O)R_(a), —C(O)NR_(a)R_(b), —C(O)OR_(a),haloalkyl, nitroalkyl, cynaoalkyl, formylalkyl, -alkylOR_(a),-alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),-alkylN(R_(b))C(O)OR_(a), -alkylN(R_(b))SO₂NR_(a)R_(b),-alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),-alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkylC(O)R_(a),-alkylC(O)NR_(a)R_(b) and R^(9a), wherein R_(a) and R_(b) are eachindependently selected from the group consisting of hydrogen, C1 alkyl,C2 alkyl, C3 alkyl, C4 alkyl and C5 alkyl, and R^(9a) is unsubstitutedor substituted pyridyl; and L, B, R¹, R^(1a), R², R^(2a), R³, R^(3a),R⁴, R⁵, R⁶, R^(6a), R⁷, R^(7a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂,Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c) nand the substituents of R^(9a) are as defined in formula (III).

For example, the present invention provides a compound of formula (III)wherein R⁴is H; R⁵ is OR¹⁶; L is —C(═O) or —C(═S); R² is alkyl; and B,R¹, R^(1a), R³, R^(3a), R⁶, R^(6a), R⁷, R^(7a), R⁹, R^(9a), R¹⁵, R¹⁶,R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m′, m″, r,t, R_(a), R_(b), R_(c) and n are as defined in formula (III).

For example, the present invention provides a compound of formula (III)wherein R⁴is OR¹⁶; R⁵ is H; L is —C(═O) or —C(═S); R² is alkyl; and B,R¹, R^(1a), R³, R^(3a), R⁶, R^(6a), R⁷, R^(7a), R⁹, R⁹, R¹⁵, R¹⁶ , R₁₀₃,R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m′, m″, r, t,R_(a), R_(b), R_(c) and n are as defined in formula (III).

For example, the present invention provides a compound of formula (III)wherein R⁴is H; R⁵ is OR¹⁶; L is —C(═O) or —C(═S); R¹ is alkyl; and B,R², R^(2a), R³, R^(3a), R⁶, R^(6a), R⁷, R^(7a), R⁹, R^(9a), R¹⁵, R¹⁶,R₁₀₃, R₁₀₄, R₁₀₅, M′, Z₁, Z₂, Q, W, M′, R_(a), R_(b), R_(c) and n are asdefined in formula (III).

For example, the present invention provides a compound of formula (III)wherein R⁴is OR¹⁶; R⁵ is H; L is —C(═O) or —C(═S); R¹ is alkyl; and B,R², R^(2a), R³, R^(3a), R⁶, R^(6a), R⁷, R^(7a), R⁹, R^(9a), R¹⁵, R¹⁶,R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″,r, t, R_(a), R_(b), R_(c) and n are as defined in formula (III).

For example, the present invention provides a compound of formula (III)wherein R⁴is H; R⁵ is OR¹⁶; L is —C(═O) or —C(═S); R³ is arylalkylwherein the aryl moiety of the arylalkyl is substituted with 0, 1, 2, 3or 4 substituents independently selected from the group consisting ofcyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,—N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,—N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),—N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂, —C(O)N(H)(alkyl),—C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH₂,-alkylN(H)(alkyl), -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂,-alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH,-alkylC(O)Oalkyl, -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl),-alkylC(O)N(alkyl)₂ and R^(3a); and B, R¹, R^(1a), R², R^(2a), R^(3a),R⁶, R^(6a), R⁷, R^(7a), R⁹, R^(9a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁,Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c)and n are as defined in formula (III).

For example, the present invention provides a compound of formula (III)wherein R⁴is OR¹⁶; R⁵ is H; L is —C(γO) or —C(═S); R³ is arylalkylwherein the aryl moiety of the arylalkyl is substituted with 0, 1, 2, 3or 4 substituents independently selected from the group consisting ofcyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,—N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,—N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),—N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂, —C(O)N(H)(alkyl),—C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH₂,-alkylN(H)(alkyl), -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂,-alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH,-alkylC(O)Oalkyl, -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl),-alkylC(O)N(alkyl)₂ and R^(3a); and B, R¹, R^(1a), R², R^(2a), R^(3a),R⁶, R^(6a), R⁷, R^(7a), R⁹, R^(9a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁,Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c)and n are as defined in formula (III).

For example, the present invention provides a compound of formula (III)wherein R⁴is H; R⁵ is OR¹⁶; L is —C(═O) or —C(═S); R⁶ is unsubstitutedor substituted arylalkyl; and B, R¹, R^(1a), R², R^(2a), R³, R^(3a), R⁷,R^(7a), R⁹, R^(9a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′,R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(a) n and thesubstituents of R⁶ are as defined in formula (III).

For example, the present invention provides a compound of formula (III)wherein R⁴is OR¹⁶; R⁵ is H; L is —C(═O) or —C(═S); R⁶ is unsubstitutedor substituted arylalkyl; and B, R¹, R^(1a), R², R^(2a), R³, R^(3a), R⁷,R^(7a), R⁹, R_(9a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′,R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c) c and thesubstituents of R⁶ are as defined in formula (III).

For example, the present invention provides a compound of formula (III)wherein R⁴is H; R⁵ is OR¹⁶; L is —C(═O) or —C(═S); R⁷ is—N(R_(b))C(O)OR_(a), C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl ortetrahydrofuranyl wherein the C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl andC5 alkyl are independently substituted with 0, 1 or 2 substituentsselected from the group consisting of halo, —OR_(a), —OC(O)R_(a),—SR_(a), —SOR_(a), —SO₂R_(a), —NR_(a)R_(b), —N(R_(b))C(O)R_(a),—N(R_(b))C(O)OR_(a), —N(R_(a))C(═N)NR_(a)R_(b),−N(R_(a))C(O)NR_(a)R_(b), —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(7a),wherein R_(a) and R_(b) are independently selected from the groupconsisting of hydrogen, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, and C5alkyl; and B, R¹, R^(1a), R², R^(2a), R³, R^(3a), R^(7a), R⁹, R^(9a),R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m,m′, m″, r, t, R_(a), R_(b), R_(c) and n are as defined in formula (III).

For example, the present invention provides a compound of formula (III)wherein R⁴is OR¹⁶; R⁵ is H; L is —C(═O) or —C(═S); R⁷ is—N(R_(b))C(O)OR_(a), C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl ortetrahydrofuranyl wherein the C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl andC5 alkyl are independently substituted with 0, 1 or 2 substituentsselected from the group consisting of halo, —OR_(a), —OC(O)R_(a),—SR_(a), —SOR_(a), —SO₂R_(a), —NR_(a)R_(b), —N(R_(b))C(O)R_(a),—N(R_(b))C(O)OR_(a), —N(R_(a))C(═N)NR_(a)R_(b),—N(R_(a))C(O)NR_(a)R_(b), —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(7a),wherein R_(a) and R_(b) are independently selected from the groupconsisting of hydrogen, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, and C5alkyl; and B, R, R¹, R^(1a), R², R^(2a), R³, R^(3a), R^(7a), R⁹, R^(9a),R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m,m′, m″, r, t, R_(a), R_(b), R_(c) and n are as defined in formula (III).

For example, the present invention provides a compound of formula (III)wherein R⁴ is H; R⁵ is OR¹⁶; L is —C(═O) or —C(═S); R⁹ is unsubstitutedor substituted aryl and B, R¹, R^(1a), R², R^(2a), R³, R^(3a), R⁶,R^(6a), R⁷, R^(7a), R^(9a), R¹⁵, R¹⁶, R¹⁰³, R¹⁰⁴, R₁₀₅, M, Z₁, R₂, M,Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b),R_(c) n and the substituents of R⁹ are as defined in formula (III).

For example, the present invention provides a compound of formula (III)wherein R⁴is OR¹⁶; R⁵ is H; L is —C(═O) or —C(═S); R⁹ is unsubstitutedor substituted aryl; and B, R¹, R^(1a), R^(2a), R³, R^(3a), R⁶, R^(6a),R⁷, R^(7a), R^(9a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′,R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c) n and thesubstituents of R⁹ are as defined in formula (III).

For example, the present invention provides a compound of formula (III)wherein R⁴is H; R⁵ is OR¹⁶; L is —C(═O) or —C(═S); R⁹ is unsubstitutedor substituted heteroaryl; and B, R¹, R^(1a), R², R^(2a), R³, R^(3a),R⁶, R^(6a), R⁷, R^(7a), R^(9a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, R₂,Q, W, M′, R₁₀₆, ₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c) n andthe substituents of R⁹ are as defined in formula (III).

For example, the present invention provides a compound of formula (III)wherein R⁴is OR¹⁶; R⁵ is H; L is —C(═O) or —C(═S); R⁹ is unsubstitutedor substituted heteroaryl; and B, R¹, R^(1a), R², R^(2a), R³, R^(3a),R⁶, R^(6a), R⁷, R^(7a), R^(9a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M′, R₁₀₆,R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c) n and thesubstituents of R⁹ are as defined in formula (III).

For example, the present invention provides a compound of formula (III)wherein R⁴is H; R⁵ is OR¹⁶; L is —C(═O) or —C(═S); R² is alkyl; R³isarylalkyl wherein the aryl moiety of the arylalkyl is substituted with 0or one R^(3a); and B, R¹, R^(1a), R^(3a), R⁶, R^(6a), R⁷, R^(7a), R⁹,R^(9a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇,R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c) and n are as defined informula (III).

For example, the present invention provides a compound of formula (III)wherein R⁴is OR¹⁶; R⁵ is H; L is —C(═O) or —C(═S); R² is alkyl; R³isarylalkyl wherein the aryl moiety of the arylalkyl is substituted with 0or one R^(3a); and B, R¹, R^(1a), R^(3a), R⁶, R^(6a), R⁷, R^(7a)R⁹,R^(9a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇,R₁₀₈q, m, m′, m″, r, t, R_(a), R_(b), R_(a) and n are as defined informula (III).

For example, the present invention provides a compound of formula (III)wherein R⁴ is H; R⁵ is OR¹⁶; L is —C(═O) or C(═S); R² is alkyl; R³ isarylalkyl wherein the aryl moiety of the arylalkyl is substituted with 0or one R^(3a), R^(3a) is aryl or heteroaryl wherein each R^(3a) issubstituted with 0, 1, 2, 3 or 4 substituents independently selectedfrom the group consisting of cyano, halo, oxo, alkyl, alkenyl, hydroxy,alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),—N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),—N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂, —C(O)N(H)(alkyl),—C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH₂,-alkylN(H)(alkyl), -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂,-alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH,-alkylC(O)Oalkyl, -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), and-alkylC(O)N(alkyl)₂; and B, R¹, R^(1a), R⁶, R^(6a), R⁷, R^(7a), R⁹,R^(9a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇,R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(a) and n are as defined informula (III).

For example, the present invention provides a compound of formula (III)wherein R⁴is OR¹⁶; R⁵ is H; L is —C(═O) or —C(═S); R² is alkyl; R³ isarylalkyl wherein the aryl moiety of the arylalkyl is substituted with 0or one R^(3a), R^(3a) is aryl or heteroaryl wherein each R^(3a) issubstituted with 0, 1, 2, 3 or 4 substituents independently selectedfrom the group consisting of cyano, halo, oxo, alkyl, alkenyl, hydroxy,alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),—N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),—N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂, —C(O)N(H)(alkyl),—C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH₂,-alkylN(H)(alkyl), -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂,-alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH,-alkylC(O)Oalkyl, -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), and-alkylC(O)N(alkyl)₂; and B, R¹, R^(1a), R⁶, R^(6a), R⁷, R^(7a), R⁹,R^(9a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇,R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c) and n are as defined informula (III).

For example, the present invention provides a compound of formula (III)wherein R⁴is H; R⁵ is OR¹⁶; L is —C(═O) or —C(═S); R² is alkyl; R³ isarylalkyl wherein the aryl moiety of the arylalkyl is substituted with 0or one R^(3a) wherein R^(3a) is unsubstituted or substituted aryl orunsubstituted or substituted heteroaryl; R⁹ is unsubstituted orsubstituted aryl or unsubstituted or substituted heteroaryl; and B, R¹,R^(1a), R⁶, R^(6a), R⁷, R^(7a), R^(9a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M,Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b),R_(c), n and the substituents of R^(3a) and R⁹ are as defined in formula(III).

For example, the present invention provides a compound of formula (III)wherein R⁴ is OR¹⁶; R⁵is H; L is —C(═O) or —C(═S); R² is alkyl; R³ isarylalkyl wherein the aryl moiety of the arylalkyl is substituted with 0or one R^(3a) wherein R^(3a) is unsubstituted or substituted aryl orunsubstituted or substituted heteroaryl; R⁹ is unsubstituted orsubstituted aryl or unsubstituted or substituted heteroaryl; and B, R¹,R^(1a), R⁶, R_(6a), R⁷, R^(7a), R^(9a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M,Z₁, Z₂, Q, W, M, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b),R_(c), n and the substituents of R^(3a) and R⁹ are as defined in formula(III).

For example, the present invention provides a compound of formula (III)wherein L is —C(═O) or —C(═S); R¹ is alkyl; R² is alkyl; R³ isunsubstituted or substituted arylalkyl; R⁴ is H; R⁵ is OR¹⁶; R⁶ isunsubstituted or substituted arylalkyl; R⁷ is —N(R_(b))C(O)OR_(a), alkylor heterocycle wherein each R⁷ is unsubstituted or substituted; R⁹ isunsubstituted or substituted aryl; and B, R^(3a), R⁶, R^(6a), R⁷,R^(7a), R^(9a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆,R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c), n and thesubstituents of R³, R⁶, R⁷ and R⁹ are as defined in formula (III).

For example, the present invention provides a compound of formula (III)wherein R¹ is alkyl; R² is alkyl; R³ is unsubstituted or substitutedarylalkyl; R⁴is OR¹⁶; R⁵ is H; L is —C(═O) or —C(═S); R⁶ isunsubstituted or substituted arylalkyl; R⁷ is —N(R_(b))C(O)OR_(a), alkylor heterocycle wherein each R⁷ is unsubstituted or substituted; R⁹ isunsubstituted or substituted aryl; and B, R^(3a), R⁶, R^(6a), R⁷,R^(7a), R^(9a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆,R₁₀₇, R₁₀₈ q, m, m′, m″, r, t, R_(a), R_(b), R_(c), n and thesubstituents of R³, R⁶, R⁷ and R⁹ are as defined in formula (III).

For example, the present invention provides a compound of formula (III)wherein R¹ is methyl, R² is 1-methylpropyl, isopropyl or tert-butyl, R³is phenylmethyl wherein the phenyl moiety of the phenylmethyl isunsubstituted or substituted with one R^(3a), wherein R^(3a) isunsubstituted or substituted pyridyl; R⁴ is H; R⁵ is OR¹⁶; L is —C(═O)or —C(═S); R⁶ is unsubstituted or substituted phenylmethyl; R⁹ isunsubstituted or substituted phenyl; and B, R^(6a), R⁷, R^(7a), R^(9a),R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m,m′, m″, r, t, R_(a), R_(b), R_(c), n and the substituents of R^(3a), R⁶and R⁹ are as defined in formula (III).

For example, the present invention provides a compound of formula (III)wherein R¹ is methyl, R² is 1-methylpropyl, isopropyl or tert-butyl, R³is phenylmethyl wherein the phenyl moiety of the phenylmethyl isunsubstituted or substituted with one R^(3a), wherein R^(3a) isunsubstituted or substituted pyridyl; R⁴ is OR¹⁶; R⁵ is H; L is —C(═O)or —C(═S); R⁶ is unsubstituted or substituted phenylmethyl; R⁹ isunsubstituted or substituted phenyl; and B, R^(6a), R⁷, R^(7a), R^(9a),R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m,m′, m″, r, t, R_(a), R_(b), R_(c), n and the substituents of R^(3a), R⁶and R⁹ are as defined in formula (III).

For example, the present invention provides a compound of formula (III)wherein R¹ is alkyl; R² is alkyl; R³ is unsubstituted or substitutedarylalkyl; L is 'C(═O) or —C(═S); R⁴ is H; R⁵ is OR¹⁶; R⁶ isunsubstituted or substituted arylalkyl; R⁷ is —N(R_(b))C(O)OR_(a), alkylor heterocycle wherein each R⁷ is unsubstituted or substituted; R⁹ isunsubstituted or substituted heteroaryl; and B, R^(3a), R^(6a), R^(7a),R^(9a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇,R₁₀₈ q, m, m′, m″, r, t, R_(a), R_(b), R_(c), n and the substituents ofR³, R⁶, R⁷ and R⁹ are as defined in formula (III).

For example, the present invention provides a compound of formula (III)wherein R¹ is alkyl; R² is alkyl; R³ is unsubstituted or substitutedarylalkyl; L is —C(═O) or —C(═S); R⁴ is OR¹⁶; R⁵is H; R⁶ isunsubstituted or substituted arylalkyl; R⁷ is —N(R_(b))C(O)OR_(a), alkylor heterocycle wherein each R⁷ is unsubstituted or substituted; R⁹ isunsubstituted or substituted heteroaryl; and B, R^(3a), R^(6a), R^(7a),R^(9a), R¹⁵, R⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈q, m, m′, m″, r, t, R_(a), R_(b), R_(c), n and the substituents of R³,R⁶, R⁷ and R⁹ are as defined in formula (III).

For example, the present invention provides a compound of formula (III)wherein R¹ is methyl, R² is 1-methylpropyl, isopropyl or tert-butyl, R³is phenylmethyl wherein the phenyl moiety of the phenylmethyl isunsubstituted or substituted with one R^(3a), wherein R^(3a) isunsubstituted or substituted pyridyl; L is —C(═O) or —C(═S); R⁴ is H; R⁵is OR¹⁶, R⁶ is unsubstituted or substituted phenylmethyl; R⁹ is thienyl,furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl,isothiazolyl, isoxazolyl, isoquinolinyl, quinolinyl, pyridyl, phenyl,imidazo[1,5,b]pyridyl, benzimiazolyl, benzothienyl, benzthiazolyl orindazolyl wherein each R⁹ is unsubstituted or substituted; and B, R⁷,R^(7a), R^(9a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆,R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c), n and thesubstituents of R^(3a), R⁶, and R⁹ are as defined in formula (III).

For example, the present invention provides a compound of formula (III)wherein R¹ is methyl, R² is 1-methylpropyl, isopropyl or tert-butyl, R³is phenylmethyl wherein the phenyl moiety of the phenylmethyl isunsubstituted or substituted with one R^(3a), wherein R^(3a) isunsubstituted or substituted pyridyl; L is —C(═O) or —C(═S); R⁴ is OR¹⁶;R⁵ is H, R⁶is unsubstituted or substituted phenylmethyl; R⁹ is thienyl,furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl,isothiazolyl, isoxazolyl, isoquinolinyl, quinolinyl, pyridyl, phenyl,imidazo[1,5,b]pyridyl, benzimiazolyl, benzothienyl, benzthiazolyl orindazolyl wherein each R⁹ is unsubstituted or substituted; and B, R⁷,R^(7a), R^(9a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, R₁₀₆, R₁₀₇, R₁₀₈,q, m, m′, m″, r, t, R_(a), R_(b), R_(c), n and the substituents ofR^(3a), R⁶, and R⁹ are as defined in formula (III).

For example, the present invention provides a compound of formula (III)wherein R¹ is alkyl; R² is alkyl; R³ is unsubstituted or substitutedarylalkyl; L is —C(═O) or —C(═S); R⁴ is H; R⁵ is OR¹⁶; R⁶ isunsubstituted or substituted arylalkyl; R⁷ is —N(R_(b))C(O)OR_(a), alkylor heterocycle wherein each R⁷ is unsubstituted or substituted; R⁹ isunsubstituted or substituted heteroaryl; each R₁₀₄ is independentlyhydrogen or alkyl; Z₁ and Z₂ are O, Q is O, W is P; and B, R^(3a),R^(6a), R^(7a), R^(9a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₅, M, M′, R₁₀₆, R₁₀₇, R₁₀₈,q, m, m′, m″, r, t, R_(a), R_(b), R_(c), n and the substituents of R³,R⁶, R⁷ and R⁹ are as defined in formula (III).

For example, the present invention provides a compound of formula (III)wherein R¹ is alkyl; R² is alkyl; R³ is unsubstituted or substitutedarylalkyl; L is —C(═O) or —C(═S); R⁴ is OR¹⁶; R⁵ is H; R⁶ isunsubstituted or substituted arylalkyl; R⁷ is —N(R_(b))C(O)OR_(a), alkylor heterocycle wherein each R⁷ is unsubstituted or substituted; R⁹ isunsubstituted or substituted heteroaryl; each R₁₀₄ is independentlyhydrogen or alkyl; Z₁ and Z₂ are O, Q is O, W is P; and B, R^(3a),R^(6a), R^(7a), R^(9a), R¹⁵, R¹⁶ , R₁₀₃, R₁₀₅, M, M′, R₁₀₆, R₁₀₇, R₁₀₈,q, m, m′, m″, r, t, R_(a), R_(b), R_(c), n and the substituents of R³,R⁶, R⁷ and R⁹ are as defined in formula (III).

For example, the present invention provides a compound of formula (III)wherein R¹ is methyl, R² is I -methylpropyl, isopropyl or tert-butyl, R³is phenylmethyl wherein the phenyl moiety of the phenylmethyl isunsubstituted or substituted with one R^(3a), wherein R^(3a) isunsubstituted or substituted pyridyl; L is —C(═O) or —C(═S); R⁴ is H; R⁵is OR¹⁶, R⁶ is phenylmethyl substituted with 0 or one R^(6a); R⁹ isthienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl,isothiazolyl, isoxazolyl, isoquinolinyl, quinolinyl, pyridyl, phenyl,imidazo[1,5,b]pyridyl, benzimiazolyl, benzothienyl, benzthiazolyl orindazolyl wherein each R⁹ is unsubstituted or substituted; each R₁₀₄ isindependently hydrogen, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl or C5alkyl; each M is independently hydrogen, C1 alkyl, C2 alkyl, C3 alkyl,C4 alkyl or C5 alkyl; Z_(i) and Z₂ are O, Q is O, W is P; and B, R⁷,R^(7a), R^(9a), R¹⁵, R¹⁶, R₁₀₃, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r,t, R_(a), R_(b), R_(c), n and the substituents of R^(3a), R^(6a), M, R⁷and R⁹ are as defined in formula (III).

For example, the present invention provides a compound of formula (III)wherein R¹ is methyl, R² is 1-methylpropyl, isopropyl or tert-butyl, R³is phenylmethyl wherein the phenyl moiety of the phenylmethyl isunsubstituted or substituted with one R^(3a), wherein R^(3a) isunsubstituted or substituted pyridyl; L is —C(═O) or —C(═S); R⁴ is OR¹⁶,R⁵ is H; R⁶ is phenylmethyl substituted with 0 or one R^(6a); R⁹ isthienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl,isothiazolyl, isoxazolyl, isoquinolinyl, quinolinyl, pyridyl, phenyl,imidazo[1,5,b]pyridyl, benzimiazolyl, benzothienyl, benzthiazolyl orindazolyl wherein each R⁹ is unsubstituted or substituted; each R₁₀₄ isindependently hydrogen, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl or C5alkyl; each M is independently hydrogen, C1 alkyl, C2 alkyl, C3 alkyl,C4 alkyl or C5 alkyl; Z_(i) and Z₂ are O, Q is O, W is P; and B, R⁷,R^(7a), R^(9a), R¹⁵, R¹⁶, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b),R_(c), n and the substituents of R³ , R^(6a), M, R⁷ and R⁹ are asdefined in formula (III).

Exemplary compounds of the present invention of formula (III) include,but not limited to, the following:

methyl(1S)-1-{[((1S,3S,4S)-1-benzyl-3-hydroxy-4-{[(2S)-3-methyl-2-(2-oxo-3-{[2-(2-pyridinyl)-1,3-thiazol-4-yl]methyl}-1-imidazolidinyl)pentanoyl]amino}-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1S,3S,4S)-1-benzyl-3-hydroxy-4-({(2S)-3-methyl-2-[2-oxo-3-)4-quinolinylmethyl)-1-imidazolidinyl]pentanoyl}amino)-5-phenylpentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1S,3S,4S)-1-benzyl-3-hydroxy-4-({(2S)-3-methyl-2-[2-oxo-3-(4-quinolinylmethyl)-1-imidazolidinyl]pentanoyl}amino)-5-phenylpentyl]amino}carbonyl)-2-methylbutylcarbamate;

methyl(1S)-1-{[((1S,3S,4S)-1-benzyl-3-hydroxy-4-{[(2S)-2-(3-{[2-(methoxymethyl)-1,3-thiazol-4-yl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,3S,4S)-1-benzyl-3-hydroxy-4-[((2S)-3-methyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,2S,4S)-1-benzyl-2-hydroxy-4-[((2S)-3-methyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,2S,4S)-1-benzyl-2-hydroxy-4-[((2S)-3-methyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenylpentyl}amino)carbonyl]-2-methylbutylcarbamate;

methyl(1S)-1-[({(1S,2S,4S)-1-benzyl-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,2S,4S)-1-benzyl-2-hydroxy-4-[((2S)-3-methyl-2-{3-[(2-methyl-1,3-thiazol-5-yl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-{[((1S,2S,4S)-1-benzyl-2-hydroxy-4-{[(2S)-3-methyl-2-(2-oxo-3-{[2-(3-pyridinyl)-1,3-thiazol-4-yl]methyl}-1-imidazolidinyl)pentanoyl]amino}-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,2S,4S)-1-benzyl-2-hydroxy-4-[((2S)-3-methyl-2-{3-[(6-methyl-3-pyrindinyl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,2S,4S)-1-benzyl-4-[((2S)-3,3-dimethyl-2-{3-[(2-methyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,2S,4S)-1-benzyl-2-hydroxy-4-[((2S)-3-methyl-2-{3-[(2-methyl-3-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-{[((1S,2S,4S)-1-benzyl-2-hydroxy-4-{[(2S)-2-(3-{[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,3S,4S)-3-hydroxy-4-[((2S)-3-methyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-{[((1S,2S,4S)-1-benzyl-4-{[(2S)-3,3-dimethyl-2-(2-oxo-3-{[2-(3-pyridinyl)-1,3-thiazol-4-yl]methyl}-1-imidazolidinyl)butanoyl]amino}-2-hydroxy-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1S,2S,4S)-1-benzyl-4-({(2S)-3,3-dimethyl-2-[2-oxo-3-(3-pyridinylmethyl)-1-imidazolidinyl]butanoyl}amino)-2-hydroxy-5-phenylpentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,3S,4S)-3-hydroxy-4-[((2S)-3-methyl-2-{3-[(2-methyl-3-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,3S,4S)-1-benzyl-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,2S,4S)-1-benzyl-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-[4-(2-pyridinyl)phenyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,2S,4S)-2-hydroxy-4-[((2S)-3-methyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1R,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,3S,4S)-4-{[(2S)-3,3-dimethyl-2-(2-oxo-3-{[2-(3-pyridinyl)-1,3-thiazol-4-yl]methyl}-1-imidazolidinyl)butanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,2S,4S)-4-{[(2S)-3,3-dimethyl-2-(2-oxo-3-{[2-(3-pyridinyl)-1,3-thiazol-4-yl]methyl}-1-imidazolidinyl)butanoyl]amino}-2-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,3S,4S)-3-hydroxy-4-({(2S)-2-[3-(imidazo[1,5-a]pyridin-3-ylmethyl)-2-oxo-1-imidazolidinyl]-3,3-dimethylbutanoyl}amino)-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,2S,4S)-2-hydroxy-4-({(2S)-2-[3-(imidazo[1,5-a]pyridin-3-ylmethyl)-2-oxo-1-imidazolidinyl]-3,3-dimethylbutanoyl}amino)-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,3S,4S)-4-({(2S)-3,3-dimethyl-2-[2-oxo-3-(4-quinolinylmethyl)-1-imidazolidinyl]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,2S,4S)-4-({(2S)-3,3-dimethyl-2-[2-oxo-3-(4-quinolinylmethyl)-1-imidazolidinyl]butanoyl}amino)-2-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,2S,4S)-2-hydroxy-4-{[(2S)-2-(3-{[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,3S,4S)-3-hydroxy-4-{[(2S)-2-(3-{[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-5-phenyl-1-[4-2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1R,3S,4S)-4-{[(2S)-3,3-dimethyl-2-(2-oxo-3-{[2-(3-pyridinyl)-1,3-thiazol-4-yl]methyl}-1-imidazolidinyl)butanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1R,3S,4S)-3-hydroxy-4-{[(2S)-2-(2-(3-{[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1R,3S,4S)-4-({(2S)-3,3-dimethyl-2-[2-oxo-3-(4-quinolinylmethyl)-1-imidazolidinyl]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1R,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(1-methyl-1H-benzimidazol-2-yl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1R,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(2-methyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,3S,4S)-4-({(2S)-3,3-dimethyl-2-[3-(2-methylbenzyl)-2-oxo-1-imidazolidinyl]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,3S,4S)-4-({(2S)-3,3-dimethyl-2-[3-(3-methylbenzyl)-2-oxo-1-imidazolidinyl]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(2-methyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-phenyl-1-[4-(3-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-1-[4-(6-methyl-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-phenyl-1-[4-(3-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,2S,4S)-4-{[(2S)-2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-2-hydroxy-5-phenyl-1-[4-(3-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,3S,4S)-3-hydroxy-4-({(2S)-2-[3-(3-methoxybenzyl)-2-oxo-1-imidazolidinyl]-3,3-dimethylbutanoyl}amino)-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1R,3S,4S)-4-{[(2S)-2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-phenyl-1-[4-(4-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-1-[4-(5-methyl-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,3S,4S)-3-hydroxy-4-({(2S)-2-[3-(2-methoxybenzyl)-2-oxo-1-imidazolidinyl]-3,3-dimethylbutanoyl}amino)-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1R,3S,4S)-4-({(2S)-3,3-dimethyl-2-[3-(2-methylbenzyl)-2-oxo-1-imidazolidinyl]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1R,3S,4S)-4-({(2S)-3,3-dimethyl-2-[3-(3-methylbenzyl)-2-oxo-1-imidazolidinyl]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1R,3S,4S)-3-hydroxy-4-({(2S)-2-[3-(2-methoxybenzyl)-2-oxo-1-imidazolidinyl]-3,3-dimethylbutanoyl}amino)-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1R,3S,4S)-3-hydroxy-4-({(2S)-2-[3-(3-methoxybenzyl)-2-oxo-1-imidazolidinyl]-3,3-dimethylbutanoyl}amino)-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-1-[4-(4-methyl-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,2S,4S)-4-{[(2S)-2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-2-hydroxy-5-phenyl-i-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(2-methyl-3-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-3-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,3S,4S)-4-({(2S)-3,3-dimethyl-2-[2-oxo-3-(3-pyridinylmethyl)-1-imidazolidinyl]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,3S,4S)-4-({(2S)-3,3-dimethyl-2-[2-oxo-3-(4-pyridinylmethyl)-1-imidazolidinyl]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,3S,4S)-4-({(2S)-3,3-dimethyl-2-[2-oxo-3-(2-pyridinylmethyl)-1-imidazolidinyl]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-1-[4-(6-methyl-3-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(2-methyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-1-[4-(5-methyl-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

-   methyl(1S)-1-[({(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2-methylbutylcarbamate;

methyl(1S)-1-[({(1S,3S,4S)-4-{[(2S)-2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-3-hydroxy-1-[4-(5-methyl-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,2S,4R)-1-benzyl-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-[4-(2-pyridinyl)phenyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,2S,4S)-2-hydroxy-4-[((2S)-3-methyl-2-{3-[(1-methyl-1H-benzimidazol-2-yl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,2S,4S)-2-hydroxy-4-[((2S)-2-{3-[(2-isopropyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}-3-methylpentanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1R,3S,4S)-3-hydroxy-4-[((2S)-3-methyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(1-methyl-1H-benzimidazol-2-yl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(1-methyl-1H-benzimidazol-2-yl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,3S,4S)-3-hydroxy-4-[((2S)-2-{3-[(2-isopropyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}-3,3-dimethylbutanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,2S,4S)-2-hydroxy-4-[((2S)-2-{3-[(2-isopropyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}-3,3-dimethylbutanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(2-methyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(2-methyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,3R,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1R,3R,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,3S,4S)-4-{[(2S)-2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-1-[4-(6-methoxy-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,3S,4S)-4-{[(2S)-2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-3-hydroxy-1-[4-(6-methoxy-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,3S,4S)-4-[((2S)-2-{3-[(6-tert-butyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}-3,3-dimethylbutanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1R,3S,4S)-3-hydroxy-4-[((2S)-2-{3-[(6-isopropyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}-3,3-dimethylbutanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1R,3S,4S)-4-[((2S)-2-{3-[(6-tert-butyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}-3,3-dimethylbutanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,2S,4S)-4-{[(2S)-2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-2-hydroxy-1-[4-(6-methoxy-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-1-[4-(6-methoxy-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,3S,4S)-4-({(2S)-2-[3-(2-aminobenzyl)-2-oxo-1-imidazolidinyl]-3,3-dimethylbutanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,3S,4S)-4-({(2S)-2-[3-(4-aminobenzyl)-2-oxo-1-imidazolidinyl]-3,3-dimethylbutanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,3S,4S)-4-({(2S)-2-[3-(3-aminobenzyl)-2oxo-1-imidazolidinyl}-3,3-dimethylbutanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-1-[4-(5-methyl-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1R,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-1-[4-(5-methyl-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,3S,4S)-3-hydroxy-4-[((2S)-2-{3-[(6-isopropyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}-3,3-dimethylbutanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,3S,4S)-1-benzyl-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-[4-(2-pyridinyl)phenyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1S,2S,4S)-1-benzyl-2-hydroxy-4-({(2S)-3-methyl-2-[2-oxo-3-(4-quinolinylmethyl)-1-imidazolidinyl]pentanoyl}amino)-5-phenylpentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1S,3S,4S)-4({(2S)-2-[3-(2-fluorobenzyl)-2-oxoimidazolidin-1-yl]-3,3-dimethylbutanoyl}amino)-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1S,3S,4S)-4({(2S)-2-[3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl]-3,3-dimethylbutanoyl}amino)-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1S,3S,4S)-4({(2S)-2-[3-(3-fluorobenzyl)-2-oxoimidazolidin-1-yl]-3,3-dimethylbutanoyl}amino)-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{2-oxo-3-[2-(trifluoromethyl)benzyl]imidazolidin-1-yl}butanoyl)amino]-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{2-oxo-3-[4-(trifluoromethyl)benzyl]imidazolidin-1-yl}butanoyl)amino]-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{2-oxo-3-[2-oxo-3-[3-(trifluoromethyl)benzyl]imidazolidin-1-yl}butanoyl)amino]-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1S,3S,4S)-4-({(2S)-2-[3-(2-amino-3-methylbenzyl)-2-oxoimidazolidin-1-yl]-3,3-dimethylbutanoyl}amino)-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1S,3S,4S)-3-hydroxy-4-({(2S)-2-[3-(3-hydroxybenzyl)-2-oxoimidazolidin-1-yl]-3,3-dimethylbutanoyl}amino)-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1S,3S,4S)-3-hydroxy-4-({(2S)-2-[3-(4-hydroxybenzyl)-2-oxoimidazolidin-1-yl]-3,3-dimethylbutanoyl}amino)-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1S,3S,4S)-3-hydroxy-4-({(2S)-2-[3-(2-hydroxybenzyloxoimidazolidin-1-yl]-3,3-dimethylbutanoyl}amino)-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1R,3S,4S)-4-{[(2S)-3,3-dimethyl-2-(2-oxoimidazolidin-1-yl)butanoyl]amino}-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1R,3S,4S)-3-hydroxy-4-{[(2S,3S)-3-methyl-2-(2-oxoimidazolidin-1-yl)pentanoyl]amino}-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1R,3S,4S)-4-{[(2S)-2-(1,1-dioxido-1,2,5-thiadiazolidin-2-yl)-3,3-dimethylbutanoyl]amino}-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1S,3S,4S)-4-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-5-phenyl-3-(phosphonooxy)-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1R,3S,4S)-4-{[(2S)-2-(3-{[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]methyl}-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-5-phenyl-3-(phosphonooxy)-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

(1S,3S)-1-((1S)-1-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-2-phenylethyl)-3-({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-4-(4-pyridin-2-ylphenyl)butyl(2S)-2-aminopropanoate;

methyl(1S)-1-({[(1R,3S,4S)-4{(2S)-3,3-dimethyl-2-[3-({6-[1-methyl-1-(phosphonooxy)ethyl]pyridin-2-yl}methyl)-2-oxoimidazolidin-1-yl]butanoyl}amino)-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

(3S,5S,8S)-3(1S)-1-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-2-phenylethyl)-8-tert-butyl-7,10-dioxo-5-(4-pyridin-2-ylbenzyl)-2,11-dioxa-6,9-diazadodec-1-yl(dimethylamino)acetate;

(1S,3S)-1-((1S)-1-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-2-phenylethyl)-3-({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-4-(4-pyridin-2-ylphenyl)butyl(phosphonooxy)methylcarbonate;

(5S,7S,10S)-54(1S)-1-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-2-phenylethyl)-10-tert-butyl-3,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-2,4,13-trioxa-8,11-diazatetradec-1-yl(dimethylamino)acetate;

(5S,8S,10S)-10-((1S)-1-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-2-phenylethyl)-5-tert-butyl-3,6,12-trioxo-8-(4-pyridin-2-ylbenzyl)-2,11-dioxa-4,7-diazapentadecan-15-oicacid;

(1S,3S)-1-((1S)-1-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-2-phenylethyl)-3-({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-4-(4-pyridin-2-ylphenyl)butyl{[ethoxy(hydroxy)phosphoryl]oxy}methyl carbonate;

methyl(1S,4S,6S)-6-((1S)-1-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-2-phenylethyl)-1-tert-butyl-10-hydroxy-10-oxido-2-oxo-4-(4-pyridin-2-ylbenzyl)-7,9,11-trioxa-3-aza-10-phosphatridec-1-ylcarbamate;

methyl(1S,4S,6S)-6-((1S)-1-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-2-phenylethyl)-1-tert-butyl-10,10-dihydroxy-10-oxido-2-oxo-4-(4-pyridin-2-ylbenzyl)-7,9-dioxa-3-aza-10-phosphadec-1-ylcarbamate;

methyl(1S,4S,6S)-6-((1S)-1-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-2-phenylethyl)-1-tert-butyl-10,10-dihydroxy-8-methyl-10-oxido-2-oxo-4-(4-pyridin-2-ylbenzyl)-7,9-dioxa-3-aza-10-phosphadec-1-ylcarbamate;and

methyl(1S,4S,5S)-4-benzyl-1-tert-butyl-5-{(2S)-2-[((2S)-3,3-dimethyl-2-{3-[(6-methylpyridin-2-yl)methyl]-2-oxoimidazolidin-1-yl}butanoyl)amino]-3-phenylpropyl}-9,9-dihydroxy-9-oxido-2-oxo-6,8-dioxa-3-aza-9-phosphanon-1-ylcarbamate;

or a pharmaceutically acceptable salt form, prodrug, or stereoisomerthereof.

In a fourth embodiment, the present invention provides a compound offormula (IV)

or a pharmaceutically acceptable salt form, prodrug or a stereoisomerthereof, wherein:

-   X is O, S or NH;-   R¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,    heterocycle, aryl or heteroaryl; wherein each R¹ is substituted with    0, 1 or 2 substituents independently selected from the group    consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl,    hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),    —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂, and    R^(1a);-   R^(1a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(1a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R² is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,    heterocycle, aryl or heteroaryl wherein each R² is substituted with    0, 1 or 2 substituents independently selected from the group    consisting of halo, —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a),    —NR_(a)R_(b), —NR_(b)C(O)R_(a)—N(R_(b))C(O)OR_(a),    —N(R_(a))C(═N)NR_(a)R_(b), —N(R_(a))C(O)NR_(a)R_(b),    —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(2a);-   R^(2a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(2a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R³ is alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, -alkylOR_(a),    -alkylSR_(a), -alkylSO_(a), -alkylSO₂R_(a), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)OR_(a),    -alkylN(R_(a))C(═N)NR_(a)R_(b), -alkylN(R_(a))C(O)NR_(a)R_(b),    -alkylC(O)NR_(a)R_(b), -alkylC(O)OR_(a), cycloalkyl,    cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle,    heterocyclealkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;    wherein the cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl,    cycloalkyl moiety of the cycloalkylalkyl, cycloalkenyl moiety of the    cycloalkenylalkyl, heterocycle moiety of the heterocyclealkyl,    heteroaryl moiety of the heteroarylalkyl and the aryl moiety of the    arylalkyl are independently substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and    R^(3a);-   R^(3a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(3a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    oxo, alkyl, alkenyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), and -alkylC(O)N(alkyl)₂;-   R⁴ is H and R⁵ is OR¹⁶; or-   R⁵ is H and R⁴ is OR¹⁶; or-   R⁴ and R⁵ are —OR¹⁶;-   R⁶ is alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, -alkylOR_(a),    -alkylSR_(a), -alkylSOR_(a), -alkylSO₂R_(a), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)OR_(a),    -alkylN(R_(a))C(═N)NR_(a)R_(b), -alkylN(R_(a))C(O)NR_(a)R_(b),    -alkylC(O)NR_(a)R_(b), -alkylC(O)OR_(a), cycloalkyl,    cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle,    heterocyclealkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;    wherein the cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl,    cycloalkyl moiety of the cycloalkylalkyl, cycloalkenyl moiety of the    cycloalkenylalkyl, heterocycle moiety of the heterocyclealkyl,    heteroaryl moiety of the heteroarylalkyl and the aryl moiety of the    arylalkyl are independently substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and    R^(6a);-   R^(6a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(6a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    oxo, alkyl, alkenyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), and -alkylC(O)N(alkyl)₂;-   R⁷ is —N(R_(b))C(O)OR_(a), alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, heterocycle, aryl or heteroaryl; wherein the alkyl,    alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl and    heteroaryl are independently substituted with 0, 1 or 2 substituents    independently selected from the group consisting of halo, —OR_(a),    —OC(O)R_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —NR_(a)R_(b),    —N(R_(b))C(O)R_(a), —N(R_(b))C(O)OR_(a), —N(R_(a))C(═N)NR_(a)R_(b),    —N(R_(a))C(O)NR_(a)R_(b), —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(7a);-   R^(7a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(7a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R¹⁰ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R¹⁰ is substituted with 0,    1, 2 or 3 substituents independently selected from the group    consisting of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro,    oxo, —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))SO₂R_(a),    —N(R_(b))SO₂NR_(a)R_(b), —N(R_(b))C(O)NR_(a)R_(b),    —N(R_(b))C(O)OR_(a), —C(O)R_(a), —C(O)NR_(a)R_(b), —C(O)OR_(a),    haloalkyl, nitroalkyl, cynaoalkyl, formylalkyl, -alkylOR_(a),    -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)OR_(a), -alkylN(R_(b))SO₂NR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkylC(O)R_(a),    -alkylC(O)NR_(a)R_(b) and R^(10a);-   R^(10a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or    heteroaryl; wherein each R^(10a) is substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹⁶ is hydrogen or R¹⁵;-   R¹⁵ is

-   R₁₀₃ is C(R₁₀₅)₂, O or —N(R₁₀₅);-   R₁₀₄ is hydrogen, alkyl, haloalkyl, alkoxycarbonyl, aminocarbonyl,    alkylaminocarbonyl or dialkylaminocarbonyl,-   each M is independently selected from the group consisting of H,    —N(R₁₀₅)₂, alkyl, alkenyl, and R₁₀₆; wherein 1 to 4 —CH₂ radicals of    the alkyl or alkenyl, other than the —CH₂ radical that is bound to    Z, is optionally replaced by a heteroatom group selected from the    group consisting of O, S, S(O), SO₂ and N(R₁₀₅); and wherein any    hydrogen in said alkyl, alkenyl or R₁₀₆ is optionally replaced with    a substituent selected from the group consisting of oxo, —OR₁₀₅,    —R₁₀₅, —N(R₁₀₅)₂, —CN, —C(O)OR₁₀₅, —C(O)N(R₁₀₅)₂, —SO₂N(R₁₀₅),    —N(R₁₀₅)C(O)R₁₀₅, —C(O)R₁₀₅, —SR₁₀₅, —S(O)R₁₀₅, —SO₂R₁₀₅, —OCF₃,    —SR₁₀₆, —SOR₁₀₆, —SO₂R₁₀₆, —N(R₁₀₅)SO₂R₁₀₅, halo, —CF₃, NO₂ and    phenyl; provided that when M is —N(R₁₀₅)₂, Z, and Z₂ are —CH₂;-   Z₁ is CH₂, O, S, —N(R₁₀₅), or, when M is absent, H;-   Z₂ is CH₂, O, S or —N(R₁₀₅);-   Q is O or S;-   W is P or S; wherein when W is S, Z₁ and Z₂ are not S;-   M′ is H, alkyl, alkenyl or R₁₀₆; wherein 1 to 4 —CH₂ radicals of the    alkyl or alkenyl is optionally replaced by a heteroatom group    selected from O, S, S(O), SO₂, or N(R₁₀₅); and wherein any hydrogen    in said alkyl, alkenyl or R₁₀₆ is optionally replaced with a    substituent selected from the group consisting of oxo, —OR₁₀₅,    —R₁₀₅, —N(R₁₀₅)₂, —CN, —C(O)OR₁₀₅, —C(O)N(R₁₀₅)₂, —SO₂N(R₁₀₅),    —N(R₁₀₅)C(O)R₁₀₅, —C(O)R₁₀₅, —SR₁₀₅, —S(O)R₁₀₅, —SO₂R₁₀₅, —OCF₃,    —SR₁₀₆, —SOR₁₀₆, —SO₂R₁₀₆, —N(R₁₀₅)SO₂R₁₀₅, halo, —CF₃ and NO₂;-   R₁₀₆ is a monocyclic or bicyclic ring system selected from the group    consisting of aryl, cycloalkyl, cycloalkenyl heteroaryl and    heterocycle; wherein any of said heteroaryl and heterocycle ring    systems contains one or more heteroatoms selected from the group    consisting of O, N, S, SO, SO₂ and N(R₁₀₅); and wherein any of said    ring system is substituted with 0, 1, 2, 3, 4, 5 or 6 substituents    selected from the group consisting of hydroxy, alkyl, alkoxy, and    —OC(O)alkyl;-   each R₁₀₅ is independently selected from the group consisting of H    or alkyl; wherein said alkyl is optionally substituted with a ring    system selected from the group consisting of aryl, cycloalkyl,    cycloalkenyl, heteroaryl and heterocycle; wherein any of said    heteroaryl and heterocycle ring systems contains one or more    heteroatoms selected from the group consisting of O, N, S, SO, SO₂,    and N(R₁₀₅); and wherein any one of said ring systems is substituted    with 0, 1, 2, 3 or 4 substituents selected from the group consisting    of oxo, —OR₁₀₅, —R₁₀₅, —N(R₁₀₅)₂, —N(R₁₀₅)C(O)R₁₀₅, —CN, —C(O)OR₁₀₅,    —C(O)N(R₁₀₅)₂, halo and —CF₃;-   each R₁₀₇ and R₁₀₈ are independently selected from the group    consisting of hydrogen and alkyl;-   q is 0 or 1;-   m is 0 or 1;-   m′ is 0 or 1;-   m″ is 0 or 1;-   r is 0, 1, 2, 3 or 4;-   t is 0 or 1;-   R_(a) and R_(b) at each occurrence are independently selected from    the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    cycloalkyl, aryl, heteroaryl and heterocycle; wherein each R_(a) and    R_(b), at each occurrence, is independently substituted with 0, 1, 2    or 3 substituents independently selected from the group consisting    of cyano, nitro, halo, oxo, hydroxy, alkoxy, alkyl, alkenyl,    alkynyl, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),    —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and R_(c);-   alternatively, R_(a) and R_(b), together with the nitrogen atom to    which they are attached, form a ring selected from the group    consisting of heteroaryl and heterocycle; wherein each of the    heteroaryl and heterocycle is independently substituted with 0, 1, 2    or 3 substituents independently selected from the group consisting    of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo,    hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),    —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, formylalkyl,    nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH₂,    -alkylN(H)(alkyl), -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂,    -alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH,    -alkylC(O)Oalkyl, -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl),    -alkylC(O)N(alkyl)₂ and R_(c); and-   R_(c) is aryl, heteroaryl or heterocycle; wherein each R_(c) is    independently substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of halo, nitro,    oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkyl-NH₂, -alkyl-N(H)(alkyl), -alkyl-N(alkyl)₂,    -alkyl-N(H)C(O)NH₂, -alkyl-N(H)C(O)N(H)(alkyl),    -alkyl-N(H)C(O)N(alkyl)₂, -alkyl-C(O)OH, -alkyl-C(O)Oalkyl,    -alkyl-C(O)NH₂, -alkyl-C(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂.

For example, the present invention provides a compound of formula (IV)wherein X is O; R⁴ is H; R⁵ is OR¹⁶; and R¹, R^(1a), R², R^(2a), R³,R^(3a), R⁶, R^(6a), R⁷, R^(7a), R¹⁰, R^(10a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄,R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a),R_(b), and R_(c) are as defined in formula (IV).

For example, the present invention provides a compound of formula (IV)wherein X is O; R⁴ is OR¹⁶; R⁵ is H; and R¹, R^(1a), R², R^(2a), R³,R^(3a), R⁶, R^(6a), R⁷, R^(7a), R¹⁰, R^(10a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄,R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a),R_(b), and R_(c) are as defined in formula (IV).

For example, the present invention provides a compound of formula (TV)wherein X is O; R⁴ is H; R⁵ is OR¹⁶; R² is alkyl; and R¹, R^(1a), R³,R^(3a), R⁶, R^(6a), R⁷, R^(7a), R¹⁰, R^(10a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄,R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a),R_(b), and R_(c) are as defined in formula (IV).

For example, the present invention provides a compound of formula (IV)wherein X is O; R⁴ is OR¹⁶; R⁵ is H; R² is alkyl; and R¹, R^(1a), R³,R^(3a), R⁶, R^(6a), R⁷, R^(7a), R¹⁰, R^(10a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄,R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a),R_(b), and R_(c) are as defined in formula (IV).

For example, the present invention provides a compound of formula (IV)wherein X is O; R⁴ is H; R⁵ is OR¹⁶; R² is alkyl and R³ is arylalkylwherein the aryl moiety of the arylalkyl is unsubstituted orsubstituted; and R¹, R^(1a), R^(3a), R⁶, R^(6a), R⁷, R^(7a), R¹⁰,R^(10a),R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇,R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c) and the substituents ofthe aryl moiety of the arylalkyl of R³ are as defined in formula (IV).

For example, the present invention provides a compound of formula (IV)wherein X is O; R⁴ is OR¹⁶; R⁵ is H; R² is alkyl and R³ is arylalkylwherein the aryl moiety of the arylalkyl is unsubstituted orsubstituted; and R¹, R^(1a), R^(3a), R⁶, R^(6a), R⁷, R^(7a), R¹⁰,R^(10a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q,m, m′, m″, r, t, R_(a), R_(b), R_(c) and the substituents of the arylmoiety of the arylalkyl of R³ are as defined in formula (IV).

For example, the present invention provides a compound of formula (IV)wherein X is O; R⁴ is H; R⁵ is OR¹⁶; R² is alkyl, R³ is arylalkylwherein the aryl moiety of the arylalkyl is unsubstituted or substitutedwith one R^(3a), and R^(3a) is aryl which is unsubstituted orsubstituted or heteroaryl which is unsubstituted or substituted; and R¹,R^(1a), R⁶, R^(6a), R⁷, R_(7a), R¹⁰, R^(10a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄,R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a),R_(b), R_(c) and the substituents of R^(3a) are as defined in formula(IV).

For example, the present invention provides a compound of formula (IV)wherein X is O; R⁴ is OR¹⁶; R⁵ is H; R² is alkyl, R³ is arylalkylwherein the aryl moiety of the arylalkyl is unsubstituted or substitutedwith one R^(3a), and R^(3a) is unsubstituted or substituted aryl orunsubstituted or substituted heteroaryl; and R¹, R^(1a), R⁶, R^(6a), R⁷,R^(7a), R¹⁰, R^(10a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′,R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c) and thesubstituents of R^(3a) are as defined in formula (IV).

For example, the present invention provides a compound of formula (IV)wherein X is O; R⁴ is H; R⁵ is OR¹⁶; R² is alkyl; R³ is arylalkylwherein the aryl moiety of the arylalkyl is unsubstituted or substitutedwith one R^(3a) , and R^(3a) is aryl or heteroaryl wherein each R^(3a)is unsubstituted or substituted; R⁶ is unsubstituted or substitutedarylalkyl; and R¹, R^(1a), R^(6a), R⁷, R^(7a), R¹⁰, R^(10a), R¹⁵, R¹⁶,R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈ , q, m, m′, m″,r, t, R_(a), R_(b), R_(c) and the substituents of R⁶ and R^(3a) are asdefined in formula (IV).

For example, the present invention provides a compound of formula (I)wherein X is O; R⁴ is OR¹⁶; R⁵ is H; R² is alkyl; R³ is arylalkylwherein the aryl moiety of the arylalkyl is unsubstituted or substitutedwith one R^(3a), and R^(3a) is aryl or heteroaryl wherein each R^(3a) isunsubstituted or substituted; R⁶ is unsubstituted or substitutedarylalkyl; and R¹, R^(1a), R^(6a), R⁷, R^(7a), R¹⁰, R^(10a), R¹⁵, R¹⁶,R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″,r, t, R_(a), R_(b), R_(c) and the substituents of R⁶ and R^(3a) are asdefined in formula (IV).

For example, the present invention provides a compound of formula (IV)wherein X is O; R⁴ is H; R⁵ is OR¹⁶; R² is alkyl; R³ is arylalkylwherein the aryl moiety of the arylalkyl is unsubstituted or substitutedwith one R^(3a), and R^(3a) is aryl or heteroaryl wherein each R^(3a) isindependently unsubstituted or substituted; R⁶ is unsubstituted orsubstituted arylalkyl, R¹ is alkyl; and R^(6a), R⁷, R^(7a), R¹⁰,R^(10a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇,R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c) and the substituents of R⁶and R^(3a) are as defined in formula (IV).

For example, the present invention provides a compound of formula (IV)wherein X is O; R⁴ is OR¹⁶; R⁵ is H; R² is alkyl; R³ is arylalkylwherein the aryl moiety of the arylalkyl is unsubstituted or substitutedwith one R^(3a), and R^(3a) is aryl or heteroaryl wherein each R_(3a) isunsubstituted or substituted; R⁶ is unsubstituted or substitutedarylalkyl, R¹ is alkyl; and R^(6a), R⁷, R^(7a), R¹⁰, R^(10a), R¹⁵, R¹⁶,R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″,r, t, R_(a), R_(b), R_(c) and the substituents of R⁶ and R^(3a) are asdefined in formula (IV).

For example, the present invention provides a compound of formula (IV)wherein X is O; R⁴ is H; R⁵ is OR¹⁶; R² is alkyl; R³ is arylalkylwherein the aryl moiety of the arylalkyl is unsubstituted or substitutedwith one R^(3a), and R^(3a) is aryl or heteroaryl wherein each R^(3a) isindependently unsubstituted or substituted; R⁶ is unsubstituted orsubstituted arylalkyl, R¹ is alkyl; R⁷ is —N(R_(b))C(O)OR_(a), alkyl orheterocycle wherein each R⁷ is independently unsubstituted orsubstituted; and R^(6a), R^(7a), R¹⁰, R^(10a), R¹⁵, R¹⁶, R₁₀₃,R₁₀₄,R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t,R_(a), R_(b), R_(c) and the substituents of R⁶, R⁷ and R^(3a) are asdefined in formula (IV).

For example, the present invention provides a compound of formula (IV)wherein X is O; R⁴ is OR¹⁶; R⁵ is H; R² is alkyl; R³ is arylalkylwherein the aryl moiety of the arylalkyl is unsubstituted or substitutedwith one R^(3a), and R^(3a) is aryl or heteroaryl wherein each R^(3a) isindependently unsubstituted or substituted; R⁶ is unsubstituted orsubstituted arylalkyl; R¹ is alkyl; R⁷ is —N(R_(b))C(O)OR_(a), alkyl orheterocycle wherein each R⁷ is independently unsubstituted orsubstituted; and R^(6a), R^(7a), R¹⁰, R^(10a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄,R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a),R_(b), R_(c) and the substituents of R⁶, R⁷ and R^(3a) are as defined informula (IV).

For example, the present invention provides a compound of formula (IV)wherein X is O; R⁴ is H; R⁵ is OR¹⁶; R³ is alkyl; R³ is arylalkylwherein the aryl moiety of the arylalkyl is unsubstituted or substitutedwith one R^(3a), and R^(3a) is aryl or heteroaryl wherein each R^(3a) isindependently unsubstituted or substituted; R⁶ is unsubstituted orsubstituted arylalkyl, R¹ is alkyl; R⁷ is —N(R_(b))C(O)OR_(a), alkyl orheterocycle wherein each R⁷ is independently unsubstituted orsubstituted; R¹⁰ is aryl or heteroaryl wherein each R¹⁰ is independentlyunsubstituted or substituted; and R^(6a), R^(7a), R^(10a), R¹⁵, R¹⁶,R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, m, m′, m″, r, t, R_(a),R_(b), R_(c) and the substituents of R⁶, R⁷, R¹⁰ and R^(3a) are asdefined in formula (IV).

For example, the present invention provides a compound of formula (IV)wherein X is O; R⁴ is OR¹⁶; R⁵is H; R² is alkyl; R³ is arylalkyl whereinthe aryl moiety of the arylalkyl is unsubstituted or substituted withone R^(3a), and R^(3a) is aryl or heteroaryl wherein each R^(3a) isindependently unsubstituted or substituted; R⁶ is unsubstituted orsubstituted arylalkyl; R¹ is alkyl; R⁷ is —N(R_(b))C(O)OR_(a), alkyl orheterocycle wherein each R⁷ is independently unsubstituted orsubstituted; R¹⁰ is aryl or heteroaryl wherein each R¹⁰ is independentlyunsubstituted or substituted; and R^(6a), R^(7a), R^(10a), R⁵, R⁶, R₁₀₃,R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t,R_(a), R_(b), R_(c) and the substituents of R⁶, R⁷, R¹⁰, R^(3a) are asdefined in formula (IV).

For example, the present invention provides a compound of formula (IV)wherein X is O; R⁴ is H; R⁵ is OR¹⁶; R² is alkyl; R³ is arylalkylwherein the aryl moiety of the arylalkyl is unsubstituted or substitutedwith one R^(3a), and R^(3a) is aryl or heteroaryl wherein each R^(3a) isindependently unsubstituted or substituted; R⁶ is unsubstituted orsubstituted arylalkyl, R¹ is alkyl; R⁷ is —N(R_(b))C(O)OR_(a), alkyl orheterocycle wherein each R⁷ is independently unsubstituted orsubstituted; R¹⁰ is aryl or heteroaryl wherein each R¹⁰ is independentlyunsubstituted or substituted; each R₁₀₄ is independently hydrogen oralkyl; each M is independently hydrogen or alkyl; Z₁ and Z₂ are O, Q isO, W is P; each R₁₀₅ is independently hydrogen or alkyl; and R^(6a),R^(7a), R^(10a), R¹⁵, R¹⁶, R₁₀₃, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r,t, R_(a), R_(b), R_(c) and the substituents of R⁶, R⁷, R¹⁰, R^(3a), andM are as defined in formula (IV).

For example, the present invention provides a compound of formula (IV)wherein X is O; R⁴ is OR¹⁶; R⁵ is H; R² is alkyl; R³is arylalkyl whereinthe aryl moiety of the arylalkyl is unsubstituted or substituted withone R^(3a), and R^(3a) is aryl or heteroaryl wherein each R^(3a) isindependently unsubstituted or substituted; R⁶ is unsubstituted orsubstituted arylalkyl; R¹ is alkyl; R⁷ is —N(R_(b))C(O)OR_(a), alkyl orheterocycle wherein each R⁷ is independently unsubstituted orsubstituted; R¹⁰ is aryl or heteroaryl wherein each R¹⁰ is independentlyunsubstituted or substituted; each R₁₀₄ is independently hydrogen oralkyl; each M is independently hydrogen, or alkyl; Z₁ and Z₂ are O, Q isO, W is P; each R₁₀₅ is independently hydrogen or alkyl; and R^(6a),R^(7a), R^(10a), R¹⁵, R¹⁶, R₁₀₃, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r,t, R_(a), R_(b), R_(c) and the substituents of R⁶, R⁷, R¹⁰, M and R^(3a)are as defined in formula (IV).

In a fifth embodiment the present invention provides a compound offormula (V)

or a pharmaceutically acceptable salt form, prodrug or a stereoisomerthereof, wherein:

-   X is O, S or NH;-   Y is O, S or NH;-   R¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,    heterocycle, aryl or heteroaryl; wherein each R¹ is substituted with    0, 1 or 2 substituents independently selected from the group    consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl,    hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),    —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂, and    R^(1a);-   R^(1a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(1a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R² is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,    heterocycle, aryl or heteroaryl; wherein each R² is substituted with    0, 1 or 2 substituents independently selected from the group    consisting of halo, —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a),    —NR_(a)R_(b), —NR_(b)C(O)R_(a)—N(R_(b))C(O)OR_(a),    —N(R_(a))C(═N)NR_(a)R_(b), —N(R_(a))C(O)NR_(a)R_(b),    —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(2a);-   R^(2a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(2a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R³ is alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, -alkylOR_(a),    -alkylSR_(a), -alkylSOR_(a), -alkylSO₂R_(a), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)OR_(a),    -alkylN(R_(a))C(═N)NR_(a)R_(b), -alkylN(R_(a))C(O)NR_(a)R_(b),    -alkylC(O)NR_(a)R_(b), -alkylC(O)OR_(a), cycloalkyl,    cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle,    heterocyclealkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;    wherein the cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl,    cycloalkyl moiety of the cycloalkylalkyl, cycloalkenyl moiety of the    cycloalkenylalkyl, heterocycle moiety of the heterocyclealkyl,    heteroaryl moiety of the heteroarylalkyl and the aryl moiety of the    arylalkyl are independently substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and    R^(3a);-   R^(3a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(3a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    oxo, alkyl, alkenyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), and -alkylC(O)N(alkyl)₂;-   R⁴ is H and R⁵ is OR¹⁶; or-   R⁵ is H and R⁴ is OR¹⁶; or-   R⁴ and R⁵ are —OR¹⁶;-   R⁶ is alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, -alkylOR_(a),    -alkylSR_(a), -alkylSOR_(a), -alkylSO₂R_(a), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)OR_(a),    -alkylN(R_(a))C(═N)NR_(a)R_(b), -alkylN(R_(a))C(O)NR_(a)R_(b),    -alkylC(O)NR_(a)R_(b), -alkylC(O)OR_(a), cycloalkyl,    cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle,    heterocyclealkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;    wherein the cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl,    cycloalkyl moiety of the cycloalkylalkyl, cycloalkenyl moiety of the    cycloalkenylalkyl, heterocycle moiety of the heterocyclealkyl,    heteroaryl moiety of the heteroarylalkyl and the aryl moiety of the    arylalkyl are independently substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and    R^(6a);-   R^(6a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(6a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    oxo, alkyl, alkenyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), and -alkylC(O)N(alkyl)₂;-   R⁷ is —N(R_(b))C(O)OR_(a), alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, heterocycle, aryl or heteroaryl; wherein the alkyl,    alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl and    heteroaryl are independently substituted with 0, 1 or 2 substituents    independently selected from the group consisting of halo, —OR_(a),    —OC(O)R_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —NR_(a)R_(b),    —N(R_(b))C(O)R_(a), —N(R_(b))C(O)OR_(a), —N(R_(a))C(═N)NR_(a)R_(b),    —N(R_(a))C(O)NR_(a)R_(b), —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(7a);-   R^(7a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(7a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R¹¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R¹¹ is substituted with 0,    1, 2 or 3 substituents independently selected from the group    consisting of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro,    oxo, —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))SO₂R_(a),    —N(R_(b))SO₂NR_(a)R_(b), —N(R_(b))C(O)NR_(a)R_(b),    —N(R_(b))C(O)OR_(a), —C(O)R_(a), —C(O)NR_(a)R_(b), —C(O)OR_(a),    haloalkyl, nitroalkyl, cynaoalkyl, formylalkyl, -alkylOR_(a),    -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)OR_(a), -alkylN(R_(b))SO₂NR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkylC(O)R_(a),    -alkylC(O)NR_(a)R_(b) and R^(11a);-   R^(11a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or    heteroaryl; wherein each R^(11a) is substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R¹⁶ is hydrogen or R¹⁵;-   R¹⁵ is

-   R₁₀₃ is C(R₁₀₅)₂, O or —N(R₁₀₅);-   R₁₀₄ is hydrogen, alkyl, haloalkyl, alkoxycarbonyl, aminocarbonyl,    alkylaminocarbonyl or dialkylaminocarbonyl,-   each M is independently selected from the group consisting of H,    —N(R₁₀₅)₂, alkyl, alkenyl, and R₁₀₆; wherein 1 to 4 —CH₂ radicals of    the alkyl or alkenyl, other than the —CH₂ radical that is bound to    Z, is optionally replaced by a heteroatom group selected from the    group consisting of O, S, S(O), SO₂ and N(R₁₀₅); and wherein any    hydrogen in said alkyl, alkenyl or R₁₀₆ is optionally replaced with    a substituent selected from the group consisting of oxo, —OR₁₀₅,    —R₁₀₅, —N(R₁₀₅)₂, —CN, —C(O)OR₁₀₅, —C(O)N(R₁₀₅)₂, —SO₂N(R₁₀₅),    —N(R₁₀₅)C(O)R₁₀₅, —C(O)R₁₀₅, —SR₁₀₅, —S(O)R₁₀₅, —SO₂R₁₀₅, —OCF₃,    —SR₁₀₆, —SOR₁₀₆, —SO₂R₁₀₆, —N(R₁₀₅)SO₂R₁₀₅, halo, —CF₃, NO₂, NO₂ and    phenyl; provided that when M is —N(R₁₀₅)₂, Z₁ and Z₂ are —CH₂;-   Z₁ is CH₂, O, S, —N(R₁₀₅), or, when M is absent, H;-   Z₂ is CH₂, O, S or —N(R₁₀₅);-   Q is O or S;-   W is P or S; wherein when W is S, Z₁ and Z₂ are not S;

M′ is H, alkyl, alkenyl or R₁₀₆; wherein 1 to 4 —CH₂ radicals of thealkyl or alkenyl is optionally replaced by a heteroatom group selectedfrom O, S, S(O), SO₂, or N(R₁₀₅); and wherein any hydrogen in saidalkyl, alkenyl or R₁₀₆ is optionally replaced with a substituentselected from the group consisting of oxo, —OR₁₀₅, —R₁₀₅, —N(R₁₀₅)₂,—CN, —C(O)OR₁₀₅, —C(O)N(R₁₀₅)₂, —SO₂N(R₁₀₅), —N(R₁₀₅)C(O)R₁₀₅,—C(O)R₁₀₅, —SR₁₀₅, —S(O)R₁₀₅, —SO₂R₁₀₅, —OCF₃, —SR₁₀₆, —SOR₁₀₆,—SO₂R₁₀₆, —N(R₁₀₅)SO₂R₁₀₅, halo, —CF₃ and NO₂;

-   R₁₀₆ is a monocyclic or bicyclic ring system selected from the group    consisting of aryl, cycloalkyl, cycloalkenyl heteroaryl and    heterocycle; wherein any of said heteroaryl and heterocycle ring    systems contains one or more heteroatoms selected from the group    consisting of O, N, S, SO, SO₂ and N(R₁₀₅); and wherein any of said    ring system is substituted with 0, 1, 2, 3, 4, 5 or 6 substituents    selected from the group consisting of hydroxy, alkyl, alkoxy, and    —OC(O)alkyl;-   each R₁₀₅ is independently selected from the group consisting of H    or alkyl; wherein said alkyl is optionally substituted with a ring    system selected from the group consisting of aryl, cycloalkyl,    cycloalkenyl, heteroaryl and heterocycle; wherein any of said    heteroaryl and heterocycle ring systems contains one or more    heteroatoms selected from the group consisting of O, N, S, SO, SO₂,    and N(R₁₀₅); and wherein any one of said ring systems is substituted    with 0, 1, 2, 3 or 4 substituents selected from the group consisting    of oxo, —OR₁₀₅, —R₁₀₅, —N(R₁₀₅)₂, —N(R₁₀₅)C(O)R₁₀₅, —CN, —C(O)OR₁₀₅,    —C(O)N(R₁₀₅)₂, halo and —CF₃;-   each R₁₀₇ and R₁₀₈ are independently selected from the group    consisting of hydrogen and alkyl;-   q is 0 or 1;-   m is 0 or 1;-   m′ is 0 or 1;-   m″ is 0 or 1;-   r is 0, 1, 2, 3or 4;-   t is 0 or 1;-   R_(a) and R_(b) at each occurrence are independently selected from    the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    cycloalkyl, aryl, heteroaryl and heterocycle; wherein each R_(a) and    R_(b), at each occurrence, is independently substituted with 0, 1, 2    or 3 substituents independently selected from the group consisting    of cyano, nitro, halo, oxo, hydroxy, alkoxy, alkyl, alkenyl,    alkynyl, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),    —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and R_(c);-   alternatively, R_(a) and R_(b), together with the nitrogen atom to    which they are attached, form a ring selected from the group    consisting of heteroaryl and heterocycle; wherein each of the    heteroaryl and heterocycle is independently substituted with 0, 1, 2    or 3 substituents independently selected from the group consisting    of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo,    hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),    —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, formylalkyl,    nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH₂,    -alkylN(H)(alkyl), -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂,    -alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH,    -alkylC(O)Oalkyl, -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl),    -alkylC(O)N(alkyl)₂ and R_(c);-   R_(c) is aryl, heteroaryl or heterocycle; wherein each R_(c) is    independently substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of halo, nitro,    oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkyl-NH₂, -alkyl-N(H)(alkyl), -alkyl-N(alkyl)₂,    -alkyl-N(H)C(O)NH₂, -alkyl-N(H)C(O)N(H)(alkyl),    -alkyl-N(H)C(O)N(alkyl)₂, -alkyl-C(O)OH, -alkyl-C(O)Oalkyl,    -alkyl-C(O)NH₂, -alkyl-C(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂; and    n is 1 or 2.

For example, the present invention provides a compound of formula (V)wherein X is O; Y is O; and R¹, R^(1a), R², R^(2a), R³, R^(3a), R⁴, R⁵,R⁶, R^(6a), R⁷, R^(7a), R¹¹, R^(11a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₄, R₁₀₅,M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t R_(a), R_(b),R_(c) and n are as defined in formula (V).

For example, the present invention provides a compound of formula (V)wherein X is O; Y is O; R⁴ is H; R⁵ is OR¹⁶;; and R¹, R^(1a), R²,R^(2a), R³, R^(3a), R⁶, R⁷, R^(7a), R¹¹, R^(11a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄,R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a),R_(b), R_(c) and n are as defined in formula (V).

For example, the present invention provides a compound of formula (V)wherein X is O; Y is O; R⁴ is OR¹⁶; R⁵ is H; and R^(1a), R², R^(2a), R³,R^(3a), R⁶, R^(6a), R⁷, R^(7a), R¹¹, R^(11a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄,R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a),R_(b), R_(c) and n are as defined in formula (V).

For example, the present invention provides a compound of formula (V)wherein X is O; Y is O; R⁴ is H; R⁵ is OR¹⁶; R² is alkyl; and R¹,R^(1a), R³, R^(3a), R⁶, R^(6a), R⁷, R^(7a), R¹¹, R^(11a), R¹⁵, R¹⁶,R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₅, q, m, m′, m″,r, t, R_(a), R_(b), R_(c) and n are as defined in formula (V).

For example, the present invention provides a compound of formula (V) Xis O; Y is O; R⁴ is OR¹⁶; R⁵ is H; R² is alkyl; and R¹, R^(1a), R³,R^(3a), R⁶, R^(6a), R⁷, R^(7a), R¹¹, R^(11a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄,R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a),R_(b), R_(c) and n are as defined in formula (V).

For example, the present invention provides a compound of formula (V)wherein X is O; Y is O; R⁴ is H; R⁵ is OR¹⁶; R² is alkyl; and R³ isarylalkyl wherein the aryl moiety of the arylalkyl is unsubstituted orsubstituted; and R¹, R^(1a), R^(3a), R⁶, R^(6a), R⁷, R^(7a), R¹¹,R^(11a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇,R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c), n and the substituents ofthe aryl moiety of the arylalkyl of R³ are as defined in formula (V).

For example, the present invention provides a compound of formula (V)wherein X is O; Y is O; R⁴ is OR¹⁶; R⁵ is H; R² is alkyl; and R³ isarylalkyl wherein the aryl moiety of the arylalkyl is unsubstituted orsubstituted; and R¹, R^(1a), R^(3a), R⁶, R^(6a), R⁷, R^(7a), R¹¹,R^(11a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇,R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c), n and the substituents ofthe aryl moiety of the arylalkyl of R³ are as defined in formula (V).

For example, the present invention provides a compound of formula (V)wherein X is O; Y is O; R⁴ is H; R⁵ is OR¹⁶; R² is alkyl; R³ isarylalkyl wherein the aryl moiety of the arylalkyl is unsubstituted orsubstituted with one R^(3a); and R¹, R^(1a), R^(3a), R⁶, R^(6a), R⁷,R^(7a), R¹¹, R^(11a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′,R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c), and n are asdefined in formula (V).

For example, the present invention provides a compound of formula (V)wherein X is O; Y is O; R⁴ is OR¹⁶; R⁵ is H; R² is alkyl; R³ isarylalkyl wherein the aryl moiety of the arylalkyl is unsubstituted orsubstituted with one R^(3a); and R¹, R^(1a), R^(3a), R⁶, R^(6a), R⁷,R^(7a), R¹¹, R^(11a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′,R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c), defined informula (V).

For example, the present invention provides a compound of formula (V)wherein X is O; Y is O; R⁴ is H; R⁵ is OR¹⁶; R² is alkyl; R³ isarylalkyl wherein the aryl moiety of the arylalkyl is unsubstituted orsubstituted with one R^(3a), wherein R^(3a) is aryl or heteroaryl andwherein each R^(3a) is independently unsubstituted or substituted; andR¹, R^(1a), R⁶, R^(6a), R⁷, R^(7a), R¹¹, R^(11a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄,R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a),R_(b), R_(c), n and substituents of R^(3a) are as defined in formula(V).

For example, the present invention provides a compound of formula (V)wherein X is O; Y is O; R⁴ is OR¹⁶; R⁵is H; R² is alkyl; R³ is arylalkylwherein the aryl moiety of the arylalkyl is unsubstituted or substitutedwith one R^(3a), wherein R^(3a) is aryl or heteroaryl and wherein eachR^(3a) is independently unsubstituted or substituted; and R¹, R^(1a),R⁶, R_(6a), R⁷, R^(7a), R¹¹, R^(11a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁,Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c),n and the substituents of R^(3a) are as defined in formula (V).

For example, the present invention provides a compound of formula (V)wherein X is O; Y is O; R⁴ is H; R⁵ is OR¹⁶; R² is alkyl; R³ isarylalkyl wherein the aryl moiety of the arylalkyl unsubstituted orsubstituted with one R^(3a), wherein R^(3a) is aryl or heteroaryl andwherein each R^(3a) is independently unsubstituted or substituted; R¹¹is aryl or heteroaryl and wherein each R¹¹ is independentlyunsubstituted or substituted; and R¹, R^(1a), R⁶, R^(6a), R⁷, R^(7a),R^(11a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇,R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c), n and the substituents ofR^(3a) and R¹¹ are as defined in formula (V).

For example, the present invention provides a compound of formula (V)wherein X is O; Y is O; R⁴ is OR¹⁶; R⁵ is H; R² is alkyl; R³is arylalkylwherein the aryl moiety of the arylalkyl is unsubstituted or substitutedwith one R^(3a), wherein R^(3a) is aryl or heteroaryl and wherein eachR^(3a) is independently unsubstituted or substituted; R¹¹ is aryl orheteroaryl and wherein each R¹¹ is independently unsubstituted orsubstituted; and R¹, R^(1a), R⁶, R^(6a), R⁷, R^(7a), R^(11a), R¹⁵, R¹⁶,R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″,r, t, R_(a), R_(b), R_(c), n and the substituents of R^(3a) and R¹¹, areas defined in formula (V).

For example, the present invention provides a compound of formula (V)wherein X is O; Y is O; R⁴ is H; R⁵ is OR¹⁶; R² is alkyl; R³ isarylalkyl wherein the aryl moiety of the arylalkyl is unsubstituted orsubstituted with one R^(3a), wherein R^(3a) is aryl or heteroaryl andwherein each R^(3a) is independently unsubstituted or substituted; R¹¹is aryl or heteroaryl and wherein each R¹¹ is independentlyunsubstituted or substituted; R⁷ is —N(R_(b))C(O)OR_(a), alkyl, orheterocycle and wherein the alkyl or heterocycle is independentlyunsubstituted or substituted; and R¹, R^(1a), R⁶, R^(6a), R^(7a),R^(11a), R¹⁵, R₁₆, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q,m, m′, m″, r, t, R_(a), R_(b), R_(c), n and the substituents of R^(3a),R⁷ and R¹¹, are as defined in formula (V).

For example, the present invention provides a compound of formula (V)wherein X is O; Y is O; R⁴ is OR¹⁶; R⁵ is H; R² is alkyl; R³ isarylalkyl wherein the aryl moiety of the arylalkyl is unsubstituted orsubstituted with one R^(3a), wherein R^(3a) is aryl or heteroaryl andwherein each R^(3a) is independently unsubstituted or substituted; R¹ isaryl or heteroaryl and wherein each R¹¹ is independently unsubstitutedor substituted; R⁷ is —N(R_(b))C(O)OR_(a), alkyl, or heterocycle andwherein the alkyl or heterocycle is independently unsubstituted orsubstituted; and R¹, R^(1a), R⁶, R^(6a), R^(7a), R^(11a), R¹⁵, R¹⁶,R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″,r, t, R_(a), R_(b), R_(c), n and the substituents of R^(3a), R⁷ and R¹¹,are as defined in formula (V).

For example, the present invention provides a compound of formula (V)wherein X is O; Y is O; R⁴ is H; R⁵ is OR¹⁶; R² is alkyl; R³ isarylalkyl wherein the aryl moiety of the arylalkyl is unsubstituted orsubstituted with one R^(3a), wherein R^(3a) is unsubstituted orsubstituted aryl or unsubstituted or substituted heteroaryl; R¹¹ isunsubstituted or substituted aryl or unsubstituted or substitutedheteroaryl; R⁷ is —N(R_(b))C(O)OR_(a), unsubstituted or substitutedalkyl, or unsubstituted or substituted heterocycle; R⁶ is unsubstitutedor substituted arylalkyl; and R¹, R^(1a), R^(6a), R^(7a), R^(11a), R¹⁵,R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′,m″, r, r, R_(a), R_(b), R_(c), n and the substituents of R^(3a), R⁶, R⁷and R¹¹, are as defined in formula (V).

For example, the present invention provides a compound of formula (V)wherein X is O; Y is O; R⁴ is OR¹⁶; R⁵ is H; R² is alkyl; R³ isarylalkyl wherein the aryl moiety of the arylalkyl is unsubstituted orsubstituted with one R^(3a), wherein R^(3a) is unsubstituted orsubstituted aryl or unsubstituted or substituted heteroaryl; R¹¹ isunsubstituted or substituted aryl or unsubstituted or substitutedheteroaryl; R⁷ is —N(R_(b))C(O)OR_(a), unsubstituted or substitutedalkyl, or unsubstituted or substituted heterocycle; R⁶ is unsubstitutedor substituted arylalkyl; and R¹, R^(1a), R^(6a), R^(7a), R^(11a), R¹⁵,R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′,m″, r, t, R_(a), R_(b), R_(c), n and the substituents of R^(3a), R⁶, R⁷and R¹¹, are as defined in formula (V).

For example, the present invention provides a compound of formula (V)wherein X is O; Y is O; R⁴ is H; R⁵ is OR¹⁶; R² is alkyl; R³ isarylalkyl wherein the aryl moiety of the arylalkyl is unsubstituted orsubstituted with one R^(3a), wherein R^(3a) is unsubstituted orsubstituted aryl or unsubstituted or substituted heteroaryl; R¹¹ isunsubstituted or substituted aryl or unsubstituted or substitutedheteroaryl; R⁷ is —N(R_(b))C(O)OR_(a), unsubstituted or substitutedalkyl or unsubstituted or substituted heterocycle; R⁶ is unsubstitutedor substituted arylalkyl; R¹ is alkyl; and R^(6a), R^(7a), R^(11a), R¹⁵,R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅ M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′,m″, r, t, R_(a), R_(b), R_(c), n and the substituents of R^(3a), R⁶, R⁷and R¹¹, are as defined in formula (V).

For example, the present invention provides a compound of formula (V)wherein X is O; Y is O; R⁴ is OR¹⁶; R⁵ is H; R² is alkyl; R³ isarylalkyl wherein the aryl moiety of the arylalkyl is unsubstituted orsubstituted with one R^(3a), wherein R^(3a) is unsubstituted orsubstituted aryl or unsubstituted or substituted heteroaryl; R¹¹ isunsubstituted or substituted aryl or unsubstituted or substitutedheteroaryl; R⁷ is —N(R_(b))C(O)OR_(a), unsubstituted or substitutedalkyl or unsubstituted or substituted heterocycle; R⁶ is unsubstitutedor substituted arylalkyl; R¹ is alkyl; and R^(6a), R^(7a), R^(11a), R¹⁵,R¹⁶ , R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′,m″, r, t, R_(a), R_(b), R_(c), n and the substituents of R^(3a), R⁶, R⁷and R¹¹ are as defined in formula (V).

For example, the present invention provides a compound of formula (V)wherein X is O; Y is O; R⁴ is H; R⁵ is OR¹⁶; R² is alkyl; R³ isarylalkyl wherein the aryl moiety of the arylalkyl is unsubstituted orsubstituted with one R^(3a), wherein R^(3a) is unsubstituted orsubstituted aryl or unsubstituted or substituted heteroaryl; R¹¹ isunsubstituted or substituted aryl or unsubstituted or substitutedheteroaryl; R⁷ is —N(R_(b))C(O)OR_(a), unsubstituted or substitutedalkyl or unsubstituted or substituted heterocycle; R⁶ is unsubstitutedor substituted arylalkyl; R¹ is alkyl; each R₁₀₄ is independentlyhydrogen or alkyl; each M is independently hydrogen or alkyl; Z₁ and Z₂are O, Q is O, W is P; each R₁₀₅ is independently hydrogen or alkyl; andR^(6a), R^(7a), R^(11a), R¹⁵, R¹⁶, R₁₀₃, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′,m″, r, t, R_(a), R_(b), R_(c), n and the substituents of R^(3a), R⁶, R⁷,M and R¹¹, are as defined in formula (V).

For example, the present invention provides a compound of formula (V)wherein X is O; Y is O; R⁴ is OR¹⁶; R⁵ is H; R² is alkyl; R³ isarylalkyl wherein the aryl moiety of the arylalkyl is unsubstituted orsubstituted with one R^(3a), wherein R^(3a) is unsubstituted orsubstituted aryl or unsubstituted or substituted heteroaryl; R¹¹ isunsubstituted or substituted aryl or unsubstituted or substitutedheteroaryl; R⁷ is —N(R_(b))C(O)OR_(a), unsubstituted or substitutedalkyl or unsubstituted or substituted heterocycle; R⁶ is unsubstitutedor substituted arylalkyl; R¹ is alkyl; each R₁₀₄ is independentlyhydrogen or alkyl; each M is independently hydrogen or alkyl; Z₁ and Z₂are O, Q is O, W is P; each R₁₀₅ is independently hydrogen or alkyl; andR^(6a), R^(7a), R^(11a), R¹⁵, R¹⁶, R₁₀₃, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′,m″, r, t, R_(a), R_(b), R_(c), n and the substituents of R^(3a), R⁶, R⁷,M and R¹¹ are as defined in formula (V).

For example, the present invention provides a compound of formula (V)wherein X is O; Y is O; R⁴ is H; R⁵ is OR¹⁶; R² is C1, C2, C3, C4 or C5alkyl; R³ is phenylmethyl wherein R^(3a) is phenyl moiety of thephenylmethyl is unsubstituted or substituted with one R^(3a), whereinR^(3a) is unsubstituted or substituted pyridyl; R¹¹ is phenyl, thienyl,furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl,isothiazolyl, isoxazolyl, isoquinolinyl, quinolinyl, pyridyl, phenyl,pyridoimidazolyl, benzimiazolyl, benzothienyl, benzthiazolyl orindazolyl wherein each R¹¹ is independently unsubstituted orsubstituted; R⁷ is —N(R_(b))C(O)OR_(a), unsubstituted or substitutedheterocycle or unsubstituted or substituted C1-C5 alkyl; R⁶ isunsubstituted or substituted phenylmethyl; R¹ is C1, C2, C3, C4 or C5alkyl; each R₁₀₄ is independently hydrogen or alkyl; each M isindependently hydrogen, or alkyl; Z₁ and Z₂ are O, Q is O, W is P; eachR₁₀₅ is independently hydrogen or alkyl; and R^(6a), R^(7a), R^(11a),R¹⁵, R¹⁶, R₁₀₃, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b),R_(a), n and the substituents of R^(3a), R⁶, R⁷, M and R¹¹ are asdefined in formula (V).

For example, the present invention provides a compound of formula (V)wherein X is O; Y is O; R⁴ is OR¹⁶; R⁵ is H; R² is C1, C2, C3, C4 or C5alkyl; R³ is phenylmethyl wherein the phenyl moiety of the phenylmethylis unsubstituted or substituted with one R^(3a), wherein R^(3a) isunsubstituted or substituted pyridyl; R¹¹ is phenyl, thienyl, furanyl,pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isothiazolyl,isoxazolyl, isoquinolinyl, quinolinyl, pyridyl, phenyl,pyridoimidazolyl, benzimiazolyl, benzothienyl, benzthiazolyl orindazolyl wherein each R¹¹ is independently unsubstituted orsubstituted; R⁷ is —N(R_(b))C(O)OR_(a), unsubstituted or substitutedheterocycle or unsubstituted or substituted C1-C5 alkyl; R⁶ isunsubstituted or substituted phenylmethyl; R¹ is C1, C2, C3, C4 or C5alkyl; each R₁₀₄ is independently hydrogen or alkyl; each M isindependently hydrogen, or alkyl; Z₁ and Z₂ are O, Q is O, W is P; eachR₁₀₅ is independently hydrogen or alkyl; and R^(6a), R^(7a), R^(11a),R¹⁵, R¹⁶, R₁₀₃, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b),R_(a), n and the substituents of R^(3a), R⁶, R⁷, M and R¹¹ are asdefined in formula (V).

Exemplary compounds of the present invention of formula (V) include, butnot limited to, the following:

methyl(1S)-1-[({(1S,3S,4S)-3-hydroxy-4-[((2S)-3-methyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2,4-dioxo-1-imidazolidinyl}pentanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,2S,4S)-2-hydroxy-4-[((2S)-3-methyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2,4-dioxo-1-imidazolidinyl}pentanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1R,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2,4-dioxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2,4-dioxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2,4-dioxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,3S,4S)-3-hydroxy-4-[((2S)-2-{3-[(2-isopropyl-1,3-thiazol-4-yl)methyl]-2,4-dioxo-1-imidazolidinyl}-3-methylpentanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;and

methyl(1S)-1-[({(1S,3S,4S)-4-{[(2S)-2-(2,4-dioxo-3-{[2-(3-pyridinyl-1,3-thiazol-4-yl]methyl}-1-imidazolidinyl)-3-methylpentanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof.

In a sixth embodiment the present invention provides a compound offormula (VI)

or a pharmaceutically acceptable salt form, prodrug or a stereoisomerthereof, wherein:

-   X is O, S or NH;-   R¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,    heterocycle, aryl or heteroaryl; wherein each R¹ is substituted with    0, 1 or 2 substituents independently selected from the group    consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl,    hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),    —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂, and    R^(1a);-   R^(1a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(1a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R² is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,    heterocycle, aryl or heteroaryl; wherein each R² is substituted with    0, 1 or 2 substituents independently selected from the group    consisting of halo, —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a),    —NR_(a)R_(b), —NR_(b)C(O)R_(a)—N(R_(b))C(O)OR_(a),    —N(R_(a))C(═N)NR_(a)R_(b), —N(R_(a))C(O)NR_(a)R_(b),    —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(2a);-   R^(1a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(2a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R³ is alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, -alkylOR_(a),    -alkylSR_(a), -alkylSOR_(a), -alkylSO₂R_(a), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)OR_(a),    -alkylN(R_(a))C(═N)NR_(a)R_(b), -alkylN(R_(a))C(O)NR_(a)R_(b),    -alkylC(O)NR_(a)R_(b), -alkylC(O)OR_(a), cycloalkyl,    cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle,    heterocyclealkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;    wherein the cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl,    cycloalkyl moiety of the cycloalkylalkyl, cycloalkenyl moiety of the    cycloalkenylalkyl, heterocycle moiety of the heterocyclealkyl,    heteroaryl moiety of the heteroarylalkyl and the aryl moiety of the    arylalkyl are independently substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and    R^(3a);-   R^(3a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(3a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    oxo, alkyl, alkenyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), and -alkylC(O)N(alkyl)₂;-   R⁴ is H and R⁵ is OR¹⁶; or-   R⁵ is H and R⁴ is OR¹⁶; or-   R⁴ and R⁵ are —OR¹⁶;-   R⁶ is alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, -alkylOR_(a),    -alkylSR_(a), -alkylSOR_(a), -alkylSO₂R_(a), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)OR_(a),    -alkylN(R_(a))C(═N)NR_(a)R_(b), -alkylN(R_(a))C(O)NR_(a)R_(b),    -alkylC(O)NR_(a)R_(b), -alkylC(O)OR_(a), cycloalkyl,    cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle,    heterocyclealkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;    wherein the cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl,    cycloalkyl moiety of the cycloalkylalkyl, cycloalkenyl moiety of the    cycloalkenylalkyl, heterocycle moiety of the heterocyclealkyl,    heteroaryl moiety of the heteroarylalkyl and the aryl moiety of the    arylalkyl are independently substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and    R^(6a);-   R^(6a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(6a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    oxo, alkyl, alkenyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), and -alkylC(O)N(alkyl)₂;-   R⁷ is —N(R_(b))C(O)OR_(a), alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, heterocycle, aryl or heteroaryl; wherein the alkyl,    alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl and    heteroaryl are independently substituted with 0, 1 or 2 substituents    independently selected from the group consisting of halo, —OR_(a),    —OC(O)R_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —NR_(a)R_(b),    —N(R_(b))C(O)R_(a), —N(R_(b))C(O)OR_(a), —N(R_(a))C(═N)NR_(a)R_(b),    —N(R_(a))C(O)NR_(a)R_(b), —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(7a);-   R^(7a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(7a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R¹² is alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl or    cycloalkenylalkyl; wherein each R¹² is substituted with 0, 1 or 2    substituents independently selected from the group consisting of    hydroxy, alkoxy and halo;-   R¹³ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R¹³ is substituted with 0,    1, 2 or 3 substituents independently selected from the group    consisting of alkyl, alkenyl, alkynyl, cyano, halo, nitro, oxo,    —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))C(O)OR_(a),    —C(O)NR_(a)R_(b), —C(O)OR_(a), haloalkyl, nitroalkyl, cynaoalkyl,    -alkylOR_(a), -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkyl-C(O)NR_(a)R_(b) and    R^(13a);-   R^(13a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or    heteroaryl; wherein each R^(13a) is substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹⁶ is hydrogen or R¹⁵;-   R¹⁵ is

-   R₁₀₃ is C(R₁₀₅)₂, O or —N(R₁₀₅);-   R₁₀₄ is hydrogen, alkyl, haloalkyl, alkoxycarbonyl, aminocarbonyl,    alkylaminocarbonyl or dialkylaminocarbonyl,-   each M is independently selected from the group consisting of H,    N(R₁₀₅)₂, alkyl, alkenyl, and R₁₀₆; wherein 1 to 4 —CH₂ radicals of    the alkyl or alkenyl, other than the —CH₂ radical that is bound to    Z, is optionally replaced by a heteroatom group selected from the    group consisting of O, S, S(O), SO₂ and N(R₁₀₅); and wherein any    hydrogen in said alkyl, alkenyl or R₁₀₆ is optionally replaced with    a substituent selected from the group consisting of oxo, —OR₁₀₅,    —R₁₀₅, —N(R₁₀₅)₂, —CN, —C(O)OR₁₀₅, —C(O)N(R₁₀₅)₂, —SO₂N(R₁₀₅),    —N(R₁₀₅)C(O)R₁₀₅, —C(O)R₁₀₅, —SR₁₀₅, —S(O)R₁₀₅, —SO₂R₁₀₅, —OCF₃,    —SR₁₀₆, —SOR₁₀₆, —SO₂R₁₀₆, —N(R₁₀₅)SO₂R₁₀₅, halo, —CF₃, NO₂ and    phenyl; provided that when M is —N(R₁₀₅)₂, Z₁ and Z₂ are —CH₂;-   Z₁ is CH₂, O, S, —N(R₁₀₅), or, when M is absent, H;-   Z₂ is CH₂, O, S or —N(R₁₀₅);-   Q is O or S;-   W is P or S; wherein when W is S, Z₁ and Z₂ are not S;-   M′ is H, alkyl, alkenyl or R₁₀₆; wherein 1 to 4 —CH₂ radicals of the    alkyl or alkenyl is optionally replaced by a heteroatom group    selected from O, S, S(O), SO₂, or N(R₁₀₅); and wherein any hydrogen    in said alkyl, alkenyl or R₁₀₆ is optionally replaced with a    substituent selected from the group consisting of oxo, —OR₁₀₅,    —R₁₀₅, —N(R₁₀₅)₂, —CN, —C(O)OR₁₀₅, —C(O)N(R₁₀₅)₂, —SO₂N(R₁₀₅),    —N(R₁₀₅)C(O)R₁₀₅, —C(O)R₁₀₅, —SR₁₀₅, —S(O)R₁₀₅, —SO₂R₁₀₅, —OCF₃,    —SR₁₀₆, —SOR₁₀₆, —SO₂R₁₀₆, —N(R₁₀₅)SO₂R₁₀₅, halo, —CF₃ and NO₂;-   R₁₀₆ is a monocyclic or bicyclic ring system selected from the group    consisting of aryl, cycloalkyl, cycloalkenyl heteroaryl and    heterocycle; wherein any of said heteroaryl and heterocycle ring    systems contains one or more heteroatoms selected from the group    consisting of O, N, S, SO, SO₂ and N(R₁₀₅); and wherein any of said    ring system is substituted with 0, 1, 2, 3, 4, 5 or 6 substituents    selected from the group consisting of hydroxy, alkyl, alkoxy, and    —OC(O)alkyl;-   each R₁₀₅ is independently selected from the group consisting of H    or alkyl; wherein said alkyl is optionally substituted with a ring    system selected from the group consisting of aryl, cycloalkyl,    cycloalkenyl, heteroaryl and heterocycle; wherein any of said    heteroaryl and heterocycle ring systems contains one or more    heteroatoms selected from the group consisting of O, N, S, SO, SO₂,    and N(R₁₀₅); and wherein any one of said ring systems is substituted    with 0, 1, 2, 3 or 4 substituents selected from the group consisting    of oxo, —OR₁₀₅, —R₁₀₅, —N(R₁₀₅)₂, —N(R₁₀₅)C(O)R₁₀₅, —CN, —C(O)OR₁₀₅,    —C(O)N(R₁₀₅)₂, halo and —CF₃; each R₁₀₇ and R₁₀₈ are independently    selected from the group consisting of hydrogen and alkyl;-   q is 0 or 1;-   m is 0 or 1;-   m′ is 0 or 1;-   m″ is 0 or 1;-   r is 0, 1, 2, 3 or 4;-   t is 0 or 1;-   R_(a) and R_(b) at each occurrence are independently selected from    the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    cycloalkyl, aryl, heteroaryl and heterocycle; wherein each R_(a),    and R_(b), at each occurrence, is independently substituted with 0,    1, 2 or 3 substituents independently selected from the group    consisting of cyano, nitro, halo, oxo, hydroxy, alkoxy, alkyl,    alkenyl, alkynyl, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),    —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and R_(c);-   alternatively, R_(a) and R_(b), together with the nitrogen atom to    which they are attached, form a ring selected from the group    consisting of heteroaryl and heterocycle; wherein each of the    heteroaryl and heterocycle is independently substituted with 0, 1, 2    or 3 substituents independently selected from the group consisting    of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo,    hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),    —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, formylalkyl,    nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH₂,    -alkylN(H)(alkyl), -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂,    -alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH,    -alkylC(O)Oalkyl, -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl),    -alkylC(O)N(alkyl)₂ and R_(c); and-   R_(c) is aryl, heteroaryl or heterocycle; wherein each R_(c) is    independently substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of halo, nitro,    oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkyl-NH₂, -alkyl-N(H)(alkyl), -alkyl-N(alkyl)₂,    -alkyl-N(H)C(O)NH₂, -alkyl-N(H)C(O)N(H)(alkyl),    -alkyl-N(H)C(O)N(alkyl)₂, -alkyl-C(O)OH, -alkyl-C(O)Oalkyl,    -alkyl-C(O)NH₂, -alkyl-C(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂.

For example, the present invention provides a compound of formula (VI)wherein R⁴ is H; R¹⁵ is OR¹⁶; and X, R¹, R^(1a), R², R^(1a), R³, R^(3a),R⁶, R^(6a), R⁷, R^(7a), R¹², R¹³, R^(13a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅,M, Z, Q, W, M′, R₁₀₆, q, m, m′, m″, r, t, R_(a), R_(b), and R_(c) are asdefined in formula (VI).

For example, the present invention provides a compound of formula (VI)wherein R⁴ is OR¹⁶; R⁵ is H; and X, R¹, R^(1a), R², R^(2a), R₃, R^(3a),R⁶, R^(6a), R⁷, R^(7a), R¹², R¹³, R^(13a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅,M, Z, Q, W, M′, R₁₀₆, q, m, m′, m″, t, R_(a), R_(b), and R_(c) are asdefined in formula (VI).

For example, the present invention provides a compound of formula (VI)wherein R⁴ is H; R⁵ is OR¹⁶; R³ is arylalkyl wherein the aryl moiety ofthe arylalkyl is unsubstituted or substituted; and X, R¹, R^(1a), R²,R^(2a), R^(3a), R⁶, R^(6a), R⁷, R^(7a), R¹², R¹³, R^(13a), R¹⁵, R¹⁶,R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″,r, t, R_(a), R_(b), R_(c), and the substituents of the aryl moiety ofarylalkyl of R³ are as defined in formula (VI).

For example, the present invention provides a compound of formula (VI)wherein R⁴ is OR¹⁶; R⁵ is H; R³ is arylalkyl wherein the aryl moiety ofthe arylalkyl is unsubstituted or substituted; and X, R¹, R^(1a), R²,R^(2a), R^(3a), R⁶, R^(6a), R⁷, R^(7a), R¹², R¹³, R^(13a), R¹⁵, R¹⁶,R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″,r, t, R_(a), R_(b), R_(c), and the substituents of the aryl moiety ofarylalkyl of R³ are as defined in formula (VI).

For example, the present invention provides a compound of formula (VI)wherein R⁴ is H; R⁵ is OR¹⁶; R³ is arylalkyl wherein the aryl moiety ofthe arylalkyl is unsubstituted or substituted with one R^(3a); and X,R¹, R^(1a), R², R^(2a), R^(3a), R⁶, R^(6a), R⁷, R^(7a), R¹², R¹³,R^(13a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇,R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), and R_(c) are defined in formula(VI).

For example, the present invention provides a compound of formula (VI)wherein R⁴ is OR¹⁶; R⁵ is H; R³ is arylalkyl wherein the aryl moiety ofthe arylalkyl is unsubstituted or substituted with one R^(3a) and X, R¹,R^(1a), R², R^(2a), R^(3a), R⁶, R^(6a), R⁷, R^(7a), R¹², R¹³, R^(13a),R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈ q, m,m′, m″, r, t, R_(a), R_(b), and R_(c) are as defined in formula (VI).

For example, the present invention provides a compound of formula (VI)wherein R⁴ is H; R⁵ is OR¹⁶; R³is arylalkyl wherein the aryl moiety ofthe arylalkyl is unsubstituted or substituted with one R^(3a), whereinR^(3a) is unsubstituted or substituted aryl or unsubstituted orsubstituted heteroaryl; and X, R¹, R^(1a), R², R^(2a), R⁶, R^(6a), R⁷,R^(7a), R¹², R¹³, R^(13a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W,M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c) andsubstituents of R^(3a) are as defined in formula (VI).

For example, the present invention provides a compound of formula (VI)wherein R⁴ is OR¹⁶; R⁵ is H; R³ is arylalkyl wherein the aryl moiety ofthe arylalkyl is unsubstituted or substituted with one R^(3a), whereinR^(3a) is unsubstituted or substituted aryl or unsubstituted orsubstituted heteroaryl; and X, R¹, R^(1a), R², R^(2a), R⁶, R^(6a), R⁷,R^(7a), R¹², R¹³, R^(13a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W,M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c) and thesubstituents of R^(3a) are as defined in formula (VI).

For example, the present invention provides a compound of formula (VI)wherein R⁴ is H; R⁵ is OR¹⁶; R³is arylalkyl wherein the aryl moiety ofthe arylalkyl is unsubstituted or substituted with one R^(3a), whereinR^(3a) is unsubstituted or substituted aryl or unsubstituted orsubstituted heteroaryl; R¹² is alkyl; and X, R¹, R^(1a), R², R^(2a), R⁶,R^(6a), R⁷, R^(7a), R¹³, R^(13a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂,Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈ q, m, m′, m″, r, t, R_(a), R_(b), R_(c) andsubstituents of R^(3a) are as defined in formula (VI).

For example, the present invention provides a compound of formula (VI)wherein R⁴ is OR¹⁶; R⁵ is H; R³ is arylalkyl wherein the aryl moiety ofthe arylalkyl is unsubstituted or substituted with one R^(3a), whereinR^(3a) is unsubstituted or substituted aryl or unsubstituted orsubstituted heteroaryl; R¹² is alkyl; and X, R¹, R^(1a), R², R^(2a), R⁶,R^(6a), R⁷, R^(7a), R¹³, R^(13a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂,Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈ q, m, m′, m″, r, t, R₁, R_(b), R_(c) andsubstituents of R^(3a) are as defined in formula (VI).

For example, the present invention provides a compound of formula (VI)wherein R⁴ is H; R⁵ is OR¹⁶; R³ is arylalkyl wherein the aryl moiety ofthe arylalkyl is unsubstituted or substituted with one R^(3a), whereinR^(3a) is unsubstituted or substituted aryl or unsubstituted orsubstituted heteroaryl; R¹² is alkyl; R¹³ is unsubstituted orsubstituted aryl or unsubstituted or substituted heteroaryl; and X, R¹,R^(1a), R², R^(2a), R⁶, R^(6a), R⁷, R^(7a), R^(13a), R¹⁵, R¹⁶, R₁₀₃,R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈ q, m, m′, m″, r, t,R_(a), R_(b), R_(c) and substituents of R^(3a) and R¹³ are as defined informula (VI).

For example, the present invention provides a compound of formula (VI)wherein R⁴ is OR¹⁶; R⁵ is H; R³ is arylalkyl wherein the aryl moiety ofthe arylalkyl is unsubstituted or substituted with one R^(3a), whereinR^(3a) is unsubstituted or substituted aryl or unsubstituted orsubstituted heteroaryl; R¹² is alkyl; R¹³ is unsubstituted orsubstituted aryl or unsubstituted or substituted heteroaryl; and X, R¹,R^(1a), R², R^(2a), R⁶, R^(6a), R⁷, R^(7a), R^(13a), R¹⁵, R¹⁶, R₁₀₃,R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈ q, m, m′, m″, r, t,R_(a), R_(b), R_(c) and the substituents of R^(3a) and R¹³ are asdefined in formula (VI).

For example, the present invention provides a compound of formula (VI)wherein R⁴ is H; R⁵ is OR¹⁶; R³ is arylalkyl wherein the aryl moiety ofthe arylalkyl is unsubstituted or substituted with one R^(3a), whereinR^(3a) is unsubstituted or substituted aryl or unsubstituted orsubstituted heteroaryl; R¹² is alkyl; R¹³ is unsubstituted orsubstituted aryl or unsubstituted or substituted heteroaryl; R² isalkyl; and X, R¹, R^(1a), R⁶, R^(6a), R⁷, R^(7a) , R^(13a), R¹⁵, R¹⁶,R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″,r, t, R_(a), R_(b), R_(a) and the substituents of R^(3a) and R¹³ are asdefined in formula (VI).

For example, the present invention provides a compound of formula (VI)wherein R⁴ is OR¹⁶; R⁵ is H; R³ is arylalkyl wherein the aryl moiety ofthe arylalkyl is unsubstituted or substituted with one R^(3a), whereinR^(3a) is unsubstituted or substituted aryl or unsubstituted orsubstituted heteroaryl; R¹² is alkyl; R¹³ is unsubstituted orsubstituted aryl or unsubstituted or substituted heteroaryl; R² isalkyl; and X, R¹, R^(1a), R⁶, R^(6a), R⁷, R^(7a), R^(13a), R¹⁵, R¹⁶,R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″,r, t, R_(a), R_(b), R_(c) and substituents of R^(3a) and R¹³ are asdefined in formula (VI).

For example, the present invention provides a compound of formula (VI)wherein R⁴ is H; R⁵is OR¹⁶; R³ is arylalkyl wherein the aryl moiety ofthe arylalkyl is unsubstituted or substituted with one R^(3a), whereinR^(3a) is unsubstituted or substituted aryl or unsubstituted orsubstituted heteroaryl; R¹² is alkyl; R¹³ is unsubstituted orsubstituted aryl or unsubstituted or substituted heteroaryl; R² isalkyl; R¹ s alkyl; and X, R⁶, R^(6a), R⁷, R^(7a), R^(13a), R¹⁵, R¹⁶,R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″,r, t, R_(a), R_(b), R_(c) and substituents of R^(3a) and R¹³ are asdefined in formula (VI).

For example, the present invention provides a compound of formula (VI)wherein R⁴ is OR¹⁶; R⁵ is H; R³ is arylalkyl wherein the aryl moiety ofthe arylalkyl is unsubstituted or substituted with one R^(3a), whereinR^(3a) is unsubstituted or substituted aryl or unsubstituted orsubstituted heteroaryl; R¹² is alkyl; R¹³ is unsubstituted orsubstituted aryl or unsubstituted or substituted heteroaryl; R² isalkyl; R¹ is alkyl; and X, R⁶, R^(6a), R⁷, R^(7a), R^(13a), R¹⁵, R¹⁶,R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m′, m″, r,t, R_(a), R_(b), R_(c) and substituents of R^(3a), and R¹³ are asdefined in formula (VI).

For example, the present invention provides a compound of formula (VI)wherein R⁴ is H; R⁵is OR¹⁶; R³ is arylalkyl wherein the aryl moiety ofthe arylalkyl is unsubstituted or substituted with one R^(3a), whereinR^(3a) is unsubstituted or substituted aryl or unsubstituted orsubstituted heteroaryl; R¹² is alkyl; R¹³ is unsubstituted orsubstituted aryl or unsubstituted or substituted heteroaryl; R² isalkyl; R¹ is alkyl; R⁶ is unsubstituted or substituted arylalkyl; and X,R^(6a), R⁷, R^(7a), R^(13a), R¹⁵, R₁₆, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q,W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c) andsubstituents of R^(3a), R¹³, and R⁶ are as defined in formula (VI).

For example, the present invention provides a compound of formula (VI)wherein R⁴ is OR¹⁶; R⁵ is H; R³ is arylalkyl wherein the aryl moiety ofthe arylalkyl is unsubstituted or substituted with one R^(3a), whereinR^(3a) is unsubstituted or substituted aryl or unsubstituted orsubstituted heteroaryl; R¹² is alkyl; R¹³ is unsubstituted orsubstituted aryl or unsubstituted or substituted heteroaryl; R² isalkyl; R¹ is alkyl; R⁶ is unsubstituted or substituted arylalkyl; and X,R^(6a), R⁷, R^(7a), R^(13a), R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q,W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c) andsubstituents of R^(3a), R¹³, and R⁶ are as defined in formula (VI).

For example, the present invention provides a compound of formula (VI)wherein R⁴is H; R⁵ is OR¹⁶; R³ is arylalkyl wherein the aryl moiety ofthe arylalkyl is unsubstituted or substituted with one R^(3a), whereinR^(3a) is unsubstituted or substituted aryl or unsubstituted orsubstituted heteroaryl; R¹² is alkyl; R¹³ is unsubstituted orsubstituted aryl or unsubstituted or substituted heteroaryl; R² isalkyl; R¹ is alkyl; R⁶ is unsubstituted or substituted arylalkyl; R⁷ is—N(R_(b))C(O)OR_(a), unsubstituted or substituted alkyl, orunsubstituted or substituted heterocycle; and X, R^(6a), R^(7a),R^(13a, R) ¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇,R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c) and substituents ofR^(3a), R¹³, R⁶ and R⁷ are as defined in formula (VI).

For example, the present invention provides a compound of formula (VI)wherein R⁴ is OR¹⁶; R⁵ is H; R³ is arylalkyl wherein the aryl moiety ofthe arylalkyl is unsubstituted or substituted with one R^(3a), whereinR^(3a) is unsubstituted or substituted aryl or unsubstituted orsubstituted heteroaryl; R¹² is alkyl; R¹³ is unsubstituted orsubstituted aryl or unsubstituted or substituted heteroaryl; R² isalkyl; R¹ is alkyl; R⁶ is unsubstituted or substituted arylalkyl; R⁷ is—N(R_(b))C(O)OR_(a), unsubstituted or substituted alkyl, orunsubstituted or substituted heterocycle; and X, R^(6a), R^(7a), R^(3a),R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m,m′, m″, r, t, R_(a), R_(b), R_(c) and substituents of R^(3a), R¹³, R⁶and R⁷ are as defined in formula (VI).

For example, the present invention provides a compound of formula (VI)wherein R⁴ is H; R⁵ is OR¹⁶; R³ is arylalkyl wherein the aryl moiety ofthe arylalkyl is unsubstituted or substituted with one R^(3a), whereinR^(3a) is unsubstituted or substituted aryl or unsubstituted orsubstituted heteroaryl; R¹² is alkyl; R¹³is unsubstituted or substitutedaryl or unsubstituted or substituted heteroaryl; R² is alkyl; R¹ isalkyl; R⁶ is unsubstituted or substituted arylalkyl; R⁷ is—N(&)C(O)OR_(a), unsubstituted or substituted alkyl, or unsubstituted orsubstituted heterocycle; X is O; each R₁₀₄ is independently hydrogen oralkyl; each M is independently hydrogen, or alkyl; Z₁ and Z₂ are O; Q isO; W is P; each R₁₀₅ is independently hydrogen or alkyl; and R^(6a),R^(7a), R^(13a), R¹⁵, R¹⁶, R₁₀₃, M′, R₁₀₆, q, R₁₀₇, R₁₀₈, q, m, m′, m″,r, t, R_(a), R_(b), R_(c) and substituents of R^(3a), R¹³, R⁶, M and R⁷are as defined in formula (VI).

For example, the present invention provides a compound of formula (VI)wherein R⁴ is OR¹⁶; R⁵is H; R³ is arylalkyl wherein the aryl moiety ofthe arylalkyl is unsubstituted or substituted with one R^(3a), whereinR^(3a) is unsubstituted or substituted aryl or unsubstituted orsubstituted heteroaryl; R¹² is alkyl; R¹³ is unsubstituted orsubstituted aryl or unsubstituted or substituted heteroaryl; R² isalkyl; R¹ is alkyl; R⁶ is unsubstituted or substituted arylalkyl; R⁷ is—N(R_(b))C(O)OR_(a), unsubstituted or substituted alkyl, orunsubstituted or substituted heterocycle; X is O; each R₁₀₄ isindependently hydrogen or alkyl; each M is independently hydrogen, oralkyl; Z₁ and Z₂ are O; Q is O; W is P; each R₁₀₅ is independentlyhydrogen or alkyl; and R^(6a), R^(7a), R^(13a), R¹⁵, R¹⁶, R₁₀₃, M′,R₁₀₆, q, R₁₀₇ , R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c) andsubstituents of R^(3a), R¹³, R⁶, M and R⁷ are as defined in formula(VI).

For example, the present invention provides a compound of formula (VI)wherein R⁴ is H; R⁵ is OR¹⁶; R³ is phenylmethyl wherein the phenylmoiety of the phenylmethyl is unsubstituted or substituted with oneR^(3a), wherein R^(3a) is unsubstituted or substituted pyridyl; R¹² isC1 alkyl, C2 alkyl or C3 alkyl; R¹³ is thienyl, furanyl, pyrrolyl,thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl,isoquinolinyl, quinolinyl, pyridyl, phenyl, pyridoimidazolyl,benzimiazolyl, benzothienyl, benzthiazolyl or indazolyl wherein each R¹³is independently unsubstituted or substituted, R² is C1 alkyl, C2 alkyl,C3 alkyl, C4 alkyl or C5 alkyl; R¹ is C1 alkyl, C2 alkyl, C3 alkyl, C4alkyl or C5 alkyl; R⁶is unsubstituted or substituted phenylmethyl; R⁷ is—N(H)C(O)OR_(a), tetrahydrofuranyl, or unsubstituted or substitutedC1-C5 alkyl, wherein R_(a) is C1-C5 alkyl; X is O; each R₁₀₄ isindependently hydrogen, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl or C5alkyl; each M is independently hydrogen C1 alkyl, C2 alkyl, C3 alkyl, C4alkyl or C5 alkyl; Z₁ and Z₂ are O; Q is O; W is P; each R₁₀₅ isindependently hydrogen, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl or C5alkyl; and R^(6a), R^(7a), R^(13a), R¹⁵, R₁₆, R₁₀₃, M′, R₁₀₆, R₁₀₇,R₁₀₈, q, m′, m″, r, t, R_(a), R_(b), R_(c) and substituents of R^(3a),R¹³, R⁶, M and R⁷ are as defined in formula (VI).

For example, the present invention provides a compound of formula (VI)wherein R⁴ is OR¹⁶; R⁵ is H; R³ is phenylmethyl wherein the phenylmoiety of the phenylmethyl is unsubstituted or substituted with oneR^(3a), wherein R^(3a) is unsubstituted or substituted pyridyl; R¹² isC1 alkyl, C2 alkyl or C3 alkyl; R¹³ is thienyl, furanyl, pyrrolyl,thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl,isoquinolinyl, quinolinyl, pyridyl, phenyl, pyridoimidazolyl,benzimiazolyl, benzothienyl, benzthiazolyl or indazolyl wherein each R¹³is independently unsubstituted or substituted; R² is C1 alkyl, C2 alkyl,C3 alkyl, C4 alkyl or C5 alkyl; R¹ is C1 alkyl, C2 alkyl, C3 alkyl, C4alkyl or C5 alkyl; R⁶is unsubstituted or substituted phenylmethyl; R⁷ is—N(H)C(O)OR_(a), tetrahydrofuranyl, or unsubstituted or substitutedC1-C5 alkyl, wherein R_(a) is C1-C5 alkyl; X is O; each R₁₀₄ isindependently hydrogen, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl or C5alkyl; each M is independently hydrogen, C1 alkyl, C2 alkyl, C3 alkyl,C4 alkyl or C5 alkyl; Z, and Z₂ are O; Q is O; W is P; each R₁₀₄ isindependently hydrogen, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl or C5alkyl; and R^(6a), R^(7a), R^(13a), R¹⁵, R¹⁶, R₁₀₃, M′, R₁₀₆, R₁₀₇,R_(108,) q, m, m′, m″, r, t, R_(a), R_(b), R_(a) and substituents ofR^(3a), R¹³, R⁶, M and R⁷ are as defined in formula (VI).

For example, the present invention provides a compound of formula (VI)wherein R⁴ is H; R⁵ is OR¹⁶; R³ is phenylmethyl wherein the phenylmoiety of the phenylmethyl is unsubstituted or substituted with oneR^(3a), wherein R^(3a) is pyridyl substituted with 0 or one substituentselected from the group consisting of methyl and methoxide; R¹² ismethyl, ethyl or n-propyl; R¹³ is thienyl, furanyl, pyrrolyl, thiazolyl,oxazolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl,isoquinolinyl, quinolinyl, pyridyl, phenyl, pyridoimidazolyl,benzimiazolyl, benzothienyl, benzthiazolyl or indazolyl wherein each R¹³is independently unsubstituted or substituted; R² is 1-methylpropyl,tert-butyl, 2-methylpropyl, 3-methylpropyl or isopropyl; R¹ is methyl,ethyl, 1-methylpropyl, tert-butyl, 2-methylpropyl, 3-methylpropyl orisopropyl; R⁶ is unsubstituted or substituted phenylmethyl; R⁷ is—N(H)C(O)OCH₃, tetrahydrofuranyl, methyl, ethyl, propyl, n-butyl,isopropyl, 1-methylpropyl, 2-methylpropyl, 3-methylpropyl, ortert-butyl; wherein each of the methyl, ethyl, propyl, n-butyl,isopropyl, l-methylpropyl, 2-methylpropyl, 3-methylpropyl, andtert-butyl are independently unsubstituted or substituted; X is O; eachR₁₀₄ is independently hydrogen, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkylor C5 alkyl; each M is independently hydrogen, C1 alkyl, C2 alkyl, C3alkyl, C4 alkyl or C5 alkyl; Z₁ and Z₂ are O; Q is O; W is P; each R₁₀₅is independently hydrogen, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl or C5alkyl; and R^(6a), R^(7a), R^(13a), R¹⁵, R¹⁶, R₁₀₃, M′, R₁₀₆, R₁₀₇,R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c) and substituents of R¹³,R⁶, M and R⁷ are as defined in formula (VI).

For example, the present invention provides a compound of formula (VI)wherein R⁴ is OR¹⁶; R⁵ is H; R³ is phenylmethyl wherein the phenylmoiety of the phenylmethyl is unsubstituted or substituted with oneR^(3a), wherein R^(3a) is pyridyl substituted with 0 or one substituentselected from the group consisting of methyl and methoxide; R¹² ismethyl, ethyl or n-propyl; R¹³ is thienyl, furanyl, pyrrolyl, thiazolyl,oxazolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl,isoquinolinyl, quinolinyl, pyridyl, phenyl, pyridoimidazolyl,benzimiazolyl, benzothienyl, benzthiazolyl or indazolyl wherein each R¹³is independently unsubstituted or substituted; R² is 1-methylpropyl,tert-butyl, 2-methylpropyl, 3-methylpropyl or isopropyl; R¹ is methyl,ethyl, 1-methylpropyl, tert-butyl, 2-methylpropyl, 3-methylpropyl orisopropyl; R⁶ is unsubstituted or substituted phenylmethyl; R⁷ is—N(H)C(O)OCH₃, tetrahydrofuranyl, methyl, ethyl, propyl, n-butyl,isopropyl, 1-methylpropyl, 2-methylpropyl, 3-methylpropyl, ortert-butyl; wherein each of the methyl, ethyl, propyl, n-butyl,isopropyl, 1-methylpropyl, 2-methylpropyl, 3-methylpropyl, andtert-butyl are independently unsubstituted or substituted; X is O; eachR₁₀₄ is independently hydrogen, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkylor C5 alkyl; each M is independently hydrogen, C1 alkyl, C2 alkyl, C3alkyl, C4 alkyl or C5 alkyl; Z₁ and Z₂ are O; Q is O; W is P; each R₁₀₅is independently hydrogen, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl or C5alkyl; and R^(6a), R^(7a), R^(13a), R¹⁵, R¹⁶, R₁₀₃, M′, R₁₀₆, R₁₀₇,R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c) and substituents of R¹³,R⁶, M and R⁷ are as defined in formula (VI).

Exemplary compounds of the present invention of formula (VI) include,but not limited, to the following:

methyl(1S,4S,6S,7S,10S)-7-benzyl-1,10-ditert-butyl-6-hydroxy-13-methyl-2,9,12-trioxo-14-phenyl-4-[4-(2-pyridinyl)benzyl]-3,8,11,13-tetraazatetradec-1-ylcarbamate;

methyl(1S,4R,6S,7S,10S)-7-benzyl-1,10-ditert-butyl-6-hydroxy-13-methyl-2,9,12-trioxo-14-phenyl-4-[4-(2-pyridinyl)benzyl]-3,8,11,13-tetraazatetradec-1-ylcarbamate;

methyl(1S,4S,6S,7S,10S)-7-benzyl-10-sec-butyl-1-tert-butyl-6-hydroxy-13-methyl-14-(2-methyl-1,3-thiazol-4-yl)-2,9,12-trioxo-4-[4-(2-pyridinyl)benzyl]-3,8,11,13-tetraazatetradec-1-ylcarbamate;and

methyl(1S,4S,5S,7S,10S)-7-benzyl-10-sec-butyl-1-tert-butyl-5-hydroxy-13-methyl-14-(2-methyl-1,3-thiazol-4-yl)-2,9,12-trioxo-4-[4-(2-pyridinyl)benzyl]-3,8,11,13-tetraazatetradec-1-ylcarbamate;or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof.

In a seventh embodiment, the present invention provides a compound offormula (VII)

or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, wherein:

-   R¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,    heterocycle, aryl or heteroaryl; wherein each R¹ is substituted with    0, 1 or 2 substituents independently selected from the group    consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl,    hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),    —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂, and    R^(1a);-   R^(1a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(1a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R² is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,    heterocycle, aryl or heteroaryl; wherein each R² is substituted with    0, 1 or 2 substituents independently selected from the group    consisting of halo, —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a),    NR_(a)R_(b), —NR_(b)C(O)R_(a)—N(R_(b))C(O)OR_(a),    —N(R_(a))C(═N)NR_(a)R_(b), —N(R_(a))C(O)NR_(a)R_(b),    —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(2a);-   R^(2a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(2a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R³ is alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, -alkylOR_(a),    -alkylSR_(a), -alkylSOR_(a), -alkylSO₂R_(a), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)OR_(a),    -alkylN(R_(a))C(═N)NR_(a)R_(b), -alkylN(R_(a))C(O)NR_(a)R_(b),    -alkylC(O)NR_(a)R_(b), -alkylC(O)OR_(a), cycloalkyl,    cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle,    heterocyclealkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;    wherein the cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl,    cycloalkyl moiety of the cycloalkylalkyl, cycloalkenyl moiety of the    cycloalkenylalkyl, heterocycle moiety of the heterocyclealkyl,    heteroaryl moiety of the heteroarylalkyl and the aryl moiety of the    arylalkyl are independently substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and    R^(3a);-   R^(3a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(3a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    oxo, alkyl, alkenyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), and -alkylC(O)N(alkyl)₂;-   R⁴ is H and R⁵ is OR¹⁶; or-   R⁵ is H and R⁴ is OR¹⁶; or-   R⁴ and R⁵ are —OR¹⁶;-   R⁶ is alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, -alkylOR_(a),    -alkylSR_(a), -alkylSOR_(a), -alkylSO₂R_(a), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)OR_(a),    -alkylN(R_(a))C(═N)NR_(a)R_(b), -alkylN(R_(a))C(O)NR_(a)R_(b),    -alkylC(O)NR_(a)R_(b), -alkylC(O)OR_(a), cycloalkyl,    cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle,    heterocyclealkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;    wherein the cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl,    cycloalkyl moiety of the cycloalkylalkyl, cycloalkenyl moiety of the    cycloalkenylalkyl, heterocycle moiety of the heterocyclealkyl,    heteroaryl moiety of the heteroarylalkyl and the aryl moiety of the    arylalkyl are independently substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and    R^(6a);-   R^(6a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(6a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    oxo, alkyl, alkenyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), and -alkylC(O)N(alkyl)₂;-   R¹⁴ is —OR_(a), -alkylOR_(a), aryl, heteroaryl or heterocycle;    wherein the aryl, heteroaryl and heterocycle are independently    substituted with 0, 1, 2, 3 or 4 substituents independently selected    from the group consisting of cyano, halo, nitro, oxo, alkyl,    alkenyl, alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂,    —SH, —S(alkyl), —SO₂(alkyl), —S(O)₂NR_(a)R_(b), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹⁶ is hydrogen or R¹⁵;-   R¹⁵ is

-   R₁₀₃ is C(R₁₀₅)₂, O or —N(R₁₀₅);-   R₁₀₄ is hydrogen, alkyl, haloalkyl, alkoxycarbonyl, aminocarbonyl,    alkylaminocarbonyl or dialkylaminocarbonyl,-   each M is independently selected from the group consisting of H,    —N(R₁₀₅)₂, alkyl, alkenyl, and R₁₀₆; wherein 1 to 4 —CH₂ radicals of    the alkyl or alkenyl, other than the —CH₂ radical that is bound to    Z, is optionally replaced by a heteroatom group selected from the    group consisting of O, S, S(O), SO₂ and N(R₁₀₅); and wherein any    hydrogen in said alkyl, alkenyl or R₁₀₆ is optionally replaced with    a substituent selected from the group consisting of oxo, —OR₁₀₅,    —R₁₀₅, —N(R₁₀₅)₂, —CN, —C(O)OR₁₀₅, —C(O)N(R₁₀₅)₂, —SO₂N(R₁₀₅),    —N(R₁₀₅)C(O)R₁₀₅, —C(O)R₁₀₅, —SR₁₀₅, —S(O)R₁₀₅, —SO₂R₁₀₅, —OCF₃,    —SR₁₀₆, —SOR₁₀₆, —SO₂R₁₀₆, —N(R₁₀₅)SO₂R₁₀₅, halo, —CF₃, NO₂ and    phenyl; provided that when M is —N(R₁₀₅)₂, Z₁ and Z₂ are —CH₂;-   Z₁ is CH₂, O, S, —N(R₁₀₅), or, when M is absent, H;-   Z₂ is CH₂, O, S or —N(R₁₀₅);-   Q is O or S;-   W is P or S; wherein when W is S, Z₁ and Z₂ are not S;-   M′ is H, alkyl, alkenyl or R₁₀₆; wherein 1 to 4 —CH₂ radicals of the    alkyl or alkenyl is optionally replaced by a heteroatom group    selected from O, S, S(O), SO₂, or N(R₁₀₅); and wherein any hydrogen    in said alkyl, alkenyl or R₁₀₆ is optionally replaced with a    substituent selected from the group consisting of oxo, —OR₁₀₅,    —R₁₀₅, —N(R₁₀₅)₂, —CN, —C(O)OR₁₀₅, —C(O)N(R₁₀₅)₂, —SO₂N(R₁₀₅),    —N(R₁₀₅)C(O)R₁₀₅, —C(O)R₁₀₅, —SR₁₀₅, —S(O)R₁₀₅, —SO₂R₁₀₅, —OCF₃,    —SR₁₀₆, —SOR₁₀₆, —SO₂R₁₀₆, —N(R₁₀₅)SO₂R₁₀₅, halo, —CF₃ and NO₂;-   R₁₀₆ is a monocyclic or bicyclic ring system selected from the group    consisting of aryl, cycloalkyl, cycloalkenyl heteroaryl and    heterocycle; wherein any of said heteroaryl and heterocycle ring    systems contains one or more heteroatoms selected from the group    consisting of O, N, S, SO, SO₂ and N(R₁₀₅); and wherein any of said    ring system is substituted with 0, 1, 2, 3, 4, 5 or 6 substituents    selected from the group consisting of hydroxy, alkyl, alkoxy, and    —OC(O)alkyl;-   each R₁₀₅ is independently selected from the group consisting of H    or alkyl; wherein said alkyl is optionally substituted with a ring    system selected from the group consisting of aryl, cycloalkyl,    cycloalkenyl, heteroaryl and heterocycle; wherein any of said    heteroaryl and heterocycle ring systems contains one or more    heteroatoms selected from the group consisting of O, N, S, SO, SO₂,    and N(R₁₀₅); and wherein any one of said ring systems is substituted    with 0, 1, 2, 3 or 4 substituents selected from the group consisting    of oxo, —OR₁₀₅, —R₁₀₅, —N(R₁₀₅)₂, —N(R₁₀₅)C(O)R₁₀₅, —CN, —C(O)OR₁₀₅,    —C(O)N(R₁₀₅)₂, halo and —CF₃; each R₁₀₇ and R₁₀₈ are independently    selected from the group consisting of hydrogen and alkyl;-   q is 0 or 1;-   m is 0 or 1;-   m′ is 0 or 1;-   m″ is 0 or 1;-   r is 0, 1, 2, 3or 4;-   t is 0 or 1;-   R_(a) and R_(b) at each occurrence are independently selected from    the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    cycloalkyl, aryl, heteroaryl and heterocycle; wherein each R_(a) and    R_(b), at each occurrence, is independently substituted with 0, 1, 2    or 3 substituents independently selected from the group consisting    of cyano, nitro, halo, oxo, hydroxy, alkoxy, alkyl, alkenyl,    alkynyl, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),    —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and R_(c);-   alternatively, R_(a) and R_(b), together with the nitrogen atom to    which they are attached, form a ring selected from the group    consisting of heteroaryl and heterocycle; wherein each of the    heteroaryl and heterocycle is independently substituted with 0, 1, 2    or 3 substituents independently selected from the group consisting    of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo,    hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),    —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, formylalkyl,    nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH₂,    -alkylN(H)(alkyl), -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂,    -alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH,    -alkylC(O)Oalkyl, -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl),    -alkylC(O)N(alkyl)₂ and R_(c); and-   R_(c) is aryl, heteroaryl or heterocycle; wherein each R_(c) is    independently substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of halo, nitro,    oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkyl-NH₂, -alkyl-N(H)(alkyl), -alkyl-N(alkyl)₂,    -alkyl-N(H)C(O)NH₂, -alkyl-N(H)C(O)N(H)(alkyl),    -alkyl-N(H)C(O)N(alkyl)₂, -alkyl-C(O)OH, -alkyl-C(O)Oalkyl,    -alkyl-C(O)NH₂, -alkyl-C(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂.

For example, the present invention provides a compound of formula (VII)wherein W is P; Q is O; Z₁ and Z₂ are O; and R¹, R^(1a), R³, R^(3a), R⁴,R⁵, R⁶, R^(6a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, M′, R₁₀₆, R₁₀₇,R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), and R_(c), are as defined informula (VII). For example, the present invention provides a compound offormula (VII) wherein R⁴ is H, R⁵ is OR¹⁶; R² is alkyl; and R¹, R^(1a),R³, R^(3a), R⁶, R^(6a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q,W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), and R_(c),are as defined in formula (VII).

For example, the present invention provides a compound of formula (VII)wherein R⁴is OR¹⁶; R⁵ is H; R² is alkyl; and R¹, R^(1a), R³, R^(3a), R⁶,R^(6a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆,R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), and R_(c), are as definedin formula (VII).

For example, the present invention provides a compound of formula (VII)wherein R⁴ is H; R⁵ is OR¹⁶; R² is alkyl; R³ is arylalkyl wherein thearyl moiety of the arylalkyl is unsubstituted or substituted; and R¹,R^(1a), R^(3a), R⁶, R^(6a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂,Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c) andthe substituents of the aryl moiety of the arylalkyl of R³ are asdefined in formula (VII).

For example, the present invention provides a compound of formula (VII)wherein R⁴ is OR¹⁶; R⁵ is H; R² is alkyl; R³ is arylalkyl wherein thearyl moiety of the arylalkyl is unsubstituted or substituted; and R¹,R^(1a), R^(3a), R⁶, R^(6a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂,Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c) andthe substituents of the aryl moiety of the arylalkyl of R³ are asdefined in formula (VII).

For example, the present invention provides a compound of formula (VII)wherein R⁴ is H; R⁵ is OR¹⁶; R² is alkyl; R³ is arylalkyl wherein thearyl moiety of the arylalkyl is unsubstituted or substituted with oneR^(3a); and R¹, R^(1a), R^(3a), R⁶, R^(6a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄,R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a),R_(b), and R_(c) are as defined in formula (VII).

For example, the present invention provides a compound of formula (VII)wherein R⁴ is OR¹⁶; R⁵ is H; R² is alkyl; R³ is arylalkyl wherein thearyl moiety of the arylalkyl is unsubstituted or substituted with oneR^(3a); and R¹, R^(1a), R^(3a), R⁶, R^(6a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄,R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a),R_(b), and R_(c) are as defined in formula (VII).

For example, the present invention provides a compound of formula (VII)wherein R⁴ is H; R⁵ is OR¹⁶; R² is alkyl; R³ is arylalkyl wherein thearyl moiety of the arylalkyl is unsubstituted or substituted with oneR^(3a), wherein R³, is unsubstituted or substituted aryl orunsubstituted or substituted heteroaryl; and R¹, R^(1a), R⁶, R^(6a),R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈,q, m, m′, m″, r, t, R_(a), R_(b), R_(c), and the substituents of R^(3a)are as defined in formula (VII).

For example, the present invention provides a compound of formula (VII)wherein R⁴ is OR^(16;) R⁵is H; R² is alkyl; R³ is arylalkyl wherein thearyl moiety of the arylalkyl is unsubstituted or substituted with oneR^(3a), wherein R^(3a) is unsubstituted or substituted aryl orunsubstituted or substituted heteroaryl; and R¹, R^(1a), R⁶, R^(6a),R¹⁴, R¹⁵, R⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈,q, m, m′, m″, r, t, R_(a), R_(b), R_(c), and the substituents of R^(3a)are as defined in formula (VII).

For example, the present invention provides a compound of formula (VII)wherein R⁴ is H; R⁵ is OR¹⁶; R² is alkyl; R³ is arylalkyl wherein thearyl moiety of the arylalkyl is unsubstituted or substituted with oneR^(3a), wherein R^(3a) is unsubstituted or substituted aryl orunsubstituted or substituted heteroaryl; R¹ is alkyl; and R⁶, R^(6a),R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈q, m, m′, m″, r, t, R_(a), R_(b), R_(c), and the substituents of R^(3a)are as defined in formula (VII).

For example, the present invention provides a compound of formula (VII)wherein R⁴ is OR¹⁶; R⁵ is H; R² is alkyl; R³ is arylalkyl wherein thearyl moiety of the arylalkyl is unsubstituted or substituted with oneR^(3a), wherein R^(3a) is unsubstituted or substituted aryl orunsubstituted or substituted heteroaryl; R¹ is alkyl; and R⁶, R^(6a),R¹⁴, R¹, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈ q,m, m′, m″, r, t, R_(a), R_(b), R_(c), and the substituents of R^(3a) areas defined in formula (VII).

For example, the present invention provides a compound of formula (VII)wherein R⁴ is H; R⁵is OR¹⁶; R² is alkyl; R³ is arylalkyl wherein thearyl moiety of the arylalkyl is unsubstituted or substituted with oneR^(3a), wherein R^(3a) is unsubstituted or substituted aryl orunsubstituted or substituted heteroaryl; R¹ is alkyl; R⁶ isunsubstituted or substituted arylalkyl; and R^(6a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃,R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈ q, m, m′, m″, r, t,R_(a), R_(b), R_(c), and the substituents of R^(3a) and R⁶ are asdefined in formula (VII).

For example, the present invention provides a compound of formula (VII)wherein R⁴ is OR¹⁶; R⁵is H; R² is alkyl; R³ is arylalkyl wherein thearyl moiety of the arylalkyl is unsubstituted or substituted with oneR^(3a), wherein R^(3a) is unsubstituted or substituted aryl orunsubstituted or substituted heteroaryl; R¹ is alkyl; R⁶ isunsubstituted or substituted arylalkyl; and R^(6a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃,R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈ q, m, m′, m″, r, t,R_(a), R_(b), R_(c), and the substituents of R^(3a) and R⁶ are asdefined in formula (VII).

For example, the present invention provides a compound of formula (VII)wherein R⁴ is H; R⁵ is OR¹⁶; R² is alkyl; R³is arylalkyl wherein thearyl moiety of the arylalkyl is unsubstituted or substituted with oneR^(3a), wherein R^(3a) is unsubstituted or substituted aryl orunsubstituted or substituted heteroaryl; R¹ is alkyl; R⁶ is arylalkylsubstituted with 0 or one R^(6a); and R^(6a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄,R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈ q, m, m′, m″, r, t, R_(a),R_(b), R_(c), and the substituents of R^(3a) are as defined in formula(VII).

For example, the present invention provides a compound of formula (VII)wherein R⁴ is OR¹⁶; R⁵ is H; R² is alkyl; R³ is arylalkyl wherein thearyl moiety of the arylalkyl is unsubstituted or substituted with oneR^(3a), wherein R^(3a) is unsubstituted or substituted aryl orunsubstituted or substituted heteroaryl; R¹ is alkyl; R⁶ is arylalkylsubstituted with 0 or one R^(6a); and R^(6a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄,R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈ q, m, m′, m″, r, t, R_(a),R_(b), R_(c), and the substituents of R^(3a) are as defined in formula(VII).

For example, the present invention provides a compound of formula (VII)wherein R⁴ is H; R⁵ is OR¹⁶; R² is alkyl; R³ is arylalkyl wherein thearyl moiety of the arylalkyl is unsubstituted or substituted with oneR^(3a), wherein R^(3a) is unsubstituted or substituted aryl orunsubstituted or substituted heteroaryl; R¹ is alkyl; R⁶ is arylalkylsubstituted with 0 or one R^(6a); each R₁₀₄ is independently hydrogen oralkyl; each R₁₀₅ is independently hydrogen or alkyl; each M isindependently hydrogen or alkyl; Z₁ and Z₂ are O; Q is O; W is P; andR^(6a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t,R_(a), R_(b), R_(c), and the substituents of R^(3a) and M are as definedin formula (VII).

For example, the present invention provides a compound of formula (VII)wherein R⁴ is OR¹⁶; R⁵ is H; R² is alkyl; R³ is arylalkyl wherein thearyl moiety of the arylalkyl is unsubstituted or substituted with oneR^(3a), wherein R^(3a) is unsubstituted or substituted aryl orunsubstituted or substituted heteroaryl; R¹ is alkyl; R⁶ is arylalkylsubstituted with 0 or one R^(6a); each R₁₀₄ is independently hydrogen oralkyl; each R₁₀₅ is independently hydrogen or alkyl; each M isindependently hydrogen or alkyl; Z₁, and Z₂ are O; Q is O; W is P; andR^(6a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t,R_(a), R_(b), R_(c), and the substituents of R^(3a) and M are as definedin formula (VII).

For example, the present invention provides a compound of formula (VII)wherein R⁴ is H; R⁵ is OR¹⁶; R² is alkyl; R³ is arylalkyl wherein thearyl moiety of the arylalkyl is unsubstituted or substituted with oneR^(3a), wherein R^(3a) is unsubstituted or substituted aryl orunsubstituted or substituted heteroaryl; R¹ is alkyl; R⁶ is arylalkylsubstituted with 0 or one R^(6a); each R₁₀₄ is independently hydrogen oralkyl; each R₁₀₅ is independently hydrogen or alkyl; each M isindependently hydrogen or alkyl; Z₁ and Z₂ are O; Q is O; W is P; R¹⁴ is—OR_(a), -alkylOR_(a), unsubstituted or substituted aryl orunsubstituted or substituted heteroaryl; and R^(6a), R¹⁵, R¹⁶, R₁₀₃, M′,R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c), and thesubstituents of R^(3a), M and R¹⁴ are as defined in formula (VII).

For example, the present invention provides a compound of formula (VII)wherein R⁴ is OR¹⁶; R⁵ is H; R² is alkyl; R³ is arylalkyl wherein thearyl moiety of the arylalkyl is unsubstituted or substituted with oneR^(3a), wherein R^(3a) is unsubstituted or substituted aryl orunsubstituted or substituted heteroaryl; R¹ is alkyl; R⁶ is arylalkylsubstituted with 0 or one R^(6a); each R₁₀₄ is independently hydrogen oralkyl; each R₁₀₅ is independently hydrogen or alkyl; each M isindependently hydrogen or alkyl; Z₁ and Z₂ are O; Q is O; W is P; R¹⁴ is—OR_(a), -alkylOR_(a), unsubstituted or substituted aryl orunsubstituted or substituted heteroaryl; and R^(6a), R¹⁵, R¹⁶, R₁₀₃, M′,R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c), and thesubstituents of R^(3a), M and R¹⁴ are as defined in formula (VII).

For example, the present invention provides a compound of formula (VII)wherein R⁴ is H; R⁵ is OR¹⁶; R² is C1 alkyl, C2 alkyl, C3 alkyl, C4alkyl or C5 alkyl; R³ is phenylmethyl wherein the phenyl moiety of thephenylmethyl is unsubstituted or substituted with one R^(3a), whereinR^(3a) is unsubstituted or substituted pyridyl; R¹ is C1 alkyl, C2alkyl, C3 alkyl, C4 alkyl or C5 alkyl; R⁶ is phenylmethyl substitutedwith 0 or one R^(6a) wherein R^(6a) is unsubstituted or substitutedpyridyl; each R₁₀₄ is independently hydrogen, C1 alkyl, C2 alkyl, C3alkyl, C4 alkyl or C5 alkyl; each R₁₀₅ is independently hydrogen, C1alkyl, C2 alkyl, C3 alkyl, C4 alkyl or C5 alkyl; each M is independentlyhydrogen, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl or C5 alkyl; Z₁ and Z₂are O; Q is O; W is P; R¹⁴ is —OR_(a), -alkylOR_(a), thienyl, furanyl,pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isothiazolyl,isoxazolyl, isoquinolinyl, quinolinyl, pyridyl, phenyl,pyridoimidazolyl, benzimiazolyl, benzothienyl, benzthiazolyl orindazolyl wherein each of the thienyl, furanyl, pyrrolyl, thiazolyl,oxazolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl,isoquinolinyl, quinolinyl, pyridyl, phenyl, pyridoimidazolyl,benzimiazolyl, benzothienyl, benzthiazolyl and indazolyl areindependently unsubstituted or substituted; and R¹⁵, R¹⁶, R₁₀₃, M′,R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c), and thesubstituents of R^(3a), R^(6a), M and R¹⁴ are as defined in formula(VII).

For example, the present invention provides a compound of formula (VII)wherein R⁴ is OR¹⁶; R⁵ is H; R² is C1 alkyl, C2 alkyl, C3 alkyl, C4alkyl or C5 alkyl; R³ is phenylmethyl wherein the phenyl moiety of thephenylmethyl is unsubstituted or substituted with one R^(3a) whereinR^(3a) is unsubstituted or substituted pyridyl; R¹ is C1 alkyl, C2alkyl, C3 alkyl, C4 alkyl or C5 alkyl; R⁶ is phenylmethyl substitutedwith 0 or one R^(6a) wherein R^(6a) is unsubstituted or substitutedpyridyl; each R₁₀₄ is independently hydrogen, C1 alkyl, C2 alkyl, C3alkyl, C4 alkyl or C5 alkyl; each R₁₀₅ is independently hydrogen, C1alkyl, C2 alkyl, C3 alkyl, C4 alkyl or C5 alkyl; each M is independentlyhydrogen, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl or C5 alkyl; Z₁ and Z₂are O; Q is O; W is P; R¹⁴ is —OR_(a), -alkylOR_(a), thienyl, furanyl,pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isothiazolyl,isoxazolyl, isoquinolinyl, quinolinyl, pyridyl, phenyl,pyridoimidazolyl, benzimiazolyl, benzothienyl, benzthiazolyl orindazolyl wherein each of the thienyl, furanyl, pyrrolyl, thiazolyl,oxazolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl,isoquinolinyl, quinolinyl, pyridyl, phenyl, pyridoimidazolyl,benzimiazolyl, benzothienyl, benzthiazolyl and indazolyl areindependently unsubstituted or substituted; and R¹⁵ , R¹⁶, R₁₀₃, M′,R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(a), and thesubstituents of R^(3a), R^(6a), M and R¹⁴ are as defined in formula(VII).

For example, the present invention provides a compound of formula (VII)wherein R⁴ is H, R⁵ is OR¹⁶, R² is C1, C2, C3, C4 or C5 alkyl, R³ isphenylmethyl substituted with wherein R^(3a) is substituted orunsubstituted pyridyl, R¹⁴ is OR_(a), -alkylOR_(a), phenyl, oxazolyl,thienyl, or pyridyl, wherein R_(a) is phenyl or hexahydro[2,3,b]furanyland wherein each of the phenyl, oxazolyl, thienyl and pyridyl isindependently unsubstituted or substituted; R⁶ is phenylmethylsubstituted with 0 or one R^(6a) wherein R^(6a) is substituted orunsubstituted pyridyl, R¹ is C1, C2, C3, C4 or C5 alkyl; and R¹⁵, R¹⁶,R₁₀₃, M′, M, R₁₀₄, R₁₀₅, R₁₀₆, R₁₀₇, R₁₀₈, Z₁, Z₂, q, m, m′, m″, r, t,R_(a), R_(b), R_(c) and the substituents of M and R¹⁴ are as defined informula (VII).

For example, the present invention provides a compound of formula (VII)wherein R⁴ is OR¹⁶, R⁵ is H, R² is C1, C2, C3, C4 or C5 alkyl, R³ isphenylmethyl substituted with 0 or one R^(3a) wherein R^(3a) issubstituted or unsubstituted pyridyl, R¹⁴ is OR_(a), -alkylOR_(a),phenyl, oxazolyl, thienyl, or pyridyl, wherein R_(a) is phenyl orhexahydro[2,3,b]furanyl and wherein each of the phenyl, oxazolyl,thienyl and pyridyl is independently unsubstituted or substituted; R⁶ isphenylmethyl substituted with 0 or one R^(6a) wherein R^(6a) issubstituted or unsubstituted pyridyl, R¹ is C1, C2, C3, C4 or C5 alkyl;and R¹⁵, R¹⁶, R₁₀₃, M′, M, R₁₀₄, R₁₀₅, R₁₀₆, R₁₀₇, R₁₀₈, Z₁, Z₂, q, m,m′, m″, r, t, R_(a), R_(b), R_(c) and the substituents of M and R¹⁴ areas defined in formula (VII).

For example, the present invention provides a compound of formula (VII)wherein R⁴ is H, R⁵ is OR¹⁶, R² is isopropyl, 1-methylpropyl ortert-butyl, R³ is phenylmethyl substituted with 0 or one R^(3a) whereinR^(3a) is pyridyl substituted with 0 or one substituent selected fromthe group consisting of methyl and methoxide, R¹⁴ is OR_(a),-alkylOR_(a), phenyl, oxazolyl, thienyl, or pyridyl, wherein R_(a) isphenyl or hexahydro[2,3,b]furanyl and wherein each of the phenyl,oxazolyl, thienyl and pyridyl is independently unsubstituted orsubstituted; 6 is phenylmethyl substituted with 0 or one R^(6a), whereinR^(6a) is pyridyl substituted with 0 or one substituent selected fromthe group consisting of methyl and methoxide; R¹ is methyl; and R¹⁵,R¹⁶, R₁₀₃, M′, M, R₁₀₄, R₁₀₅, R₁₀₆, R₁₀₇, R₁₀₈, Z₁, Z₂, q, m, m′, m″, r,t, R_(a), R_(b), R_(c), and the substituents of M and R¹⁴ are as definedin formula (VII).

For example, the present invention provides a compound of formula (VII)wherein R⁴ is OR¹⁶, R⁵ is H, R² is isopropyl, 1-methylpropyl ortert-butyl, R³ is phenylmethyl substituted with 0 or one R^(3a) whereinR^(3a) is pyridyl substituted with 0 or one substituent selected fromthe group consisting of methyl and methoxide, R¹⁴ is OR_(a),-alkylOR_(a), phenyl, oxazolyl, thienyl, or pyridyl, wherein R_(a) isphenyl or hexahydro[2,3,b] furanyl and wherein each of the phenyl,oxazolyl, thienyl and pyridyl is independently unsubstituted orsubstituted; R⁶ is phenylmethyl substituted with 0 or one R^(6a),wherein R^(6a) is pyridyl substituted with 0 or one substituent selectedfrom the group consisting of methyl and methoxide; R¹ is methyl; andR¹⁵, R¹⁶, R₁₀₃, M′, M, R₁₀₄, R₁₀₅, R₁₀₆, R₁₀₇, R₁₀₈, Z₁, Z₂, q, m, m′,m″, r, t, R_(a), R_(b), R_(c), and the substituents of M and R¹⁴ are asdefined in formula (VII).

Exemplary compounds of the present invention of formula (VII) include,but not limited to, the following:

(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl(1S,3S,4S)-1-benzyl-3-hydroxy-4-({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-5-[4-(2-pyridinyl)phenyl]pentylcarbamate;

(3R,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-yl(1S,3S,4S)-1-benzyl-3-hydroxy-4-({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-5-[4-(2-pyridinyl)phenyl]pentylcarbamate;

(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl(1S,2S,4S)-1-benzyl-2-hydroxy-4-({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-5-[4-(2-pyridinyl)phenyl]pentylcarbamate;

(3R,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-yl(1S,2S,4S)-1-benzyl-2-hydroxy-4-({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-5-[4-(2-pyridinyl)phenyl]pentylcarbamate;

methyl(1S)-1-[({(1S,3S,4S)-4-{[(2,6-dimethylphenoxy)acetyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,2S,4S)-4-{[(2,6-dimethylphenoxy)acetyl]amino}-2-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl(1S,2S,4R)-1-benzyl-2-hydroxy-4-({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-5-[4-(2-pyridinyl)phenyl]pentylcarbamate;

(3R,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-yl(1S,2S,4R)-1-benzyl-2-hydroxy-4-({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-5-[4-(2-pyridinyl)phenyl]pentylcarbamate;

methyl(1S)-1-[({(1R,3S,4S)-4-{[(2,6-dimethylphenoxy)acetyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1R)-1-{[((1S,2S,4S)-4-{[4-(aminosulfonyl)benzoyl]amino}-1-benzyl-2-hydroxy-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1R,3S,4S)-4-[(4-chloro-2-methylbenzoyl)amino]-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1R,3S,4S)-3-hydroxy-4-[(4-methoxy-2-methylbenzoyl)amino]-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1R,3S,4S)-3-hydroxy-4-[(2-methylbenzoyl)amino]-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-{[((1S,2S,4S)-4-{[3-(aminosulfonyl)benzoyl]amino}-1-benzyl-2-hydroxy-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1S,3S,4S)-4-[(3-chloro-2-methylbenzoyl)amino]-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1S,3S,4S)-3-hydroxy-4-[(3-hydroxy-2-methylbenzoyl)amino]-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1S,3S,4S)-3-hydroxy-4-{[(3-methylisoxazol-4-yl)carbonyl]amino}-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-({[(1S,3S,4S)-4-{[(3,5-dimethylisoxazol-4-yl)carbonyl]amino}-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,2S,4S)-1-benzyl-2-hydroxy-5-phenyl-4-[(thien-2-ylcarbonyl)amino]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-[({(1S,2S,4S)-1-benzyl-2-hydroxy-5-phenyl-4-[(thien-3-ylcarbonyl)amino]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;

methyl(1S)-1-{[((1S,2S,4S)-1-benzyl-2-hydroxy-4-{[(3-methylthien-2-yl)carbonyl]amino}-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamate;

methyl(1S)-1-{[((1S,2S,4S)-1-benzyl-2-hydroxy-4-{[(5-methylthien-2-yl)carbonyl]amino}-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamate;

methyl(1S)-1-{[((1S,2S,4S)-1-benzyl-2-hydroxy-{[(1-methyl-1H-pyrrol-2-yl)carbonyl]amino}-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamate;and

methyl(1S)-1-{[((1S,2S,4S)-1-benzyl-4-{[(3,5-dimethylisoxazol-4-yl)carbonyl]amino}-2-hydroxy-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamate;

or a pharmaceutically acceptable salt form, prodrug or stereoisomer,thereof.

In an eighth embodiment the present invention provides a compound offormula (VIII)

or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, wherein:

-   A is

-   X is O, S or NH;-   Y is O, S or NH;-   B is H or —CH₂R⁹;-   L is —C(═O), —C(═S), —C(═NH) or —S(O)₂;-   R^(A) is —N(H)C(O)R⁸, —O(R_(a)), —OC(O)OR_(a), —NR_(a)R_(b),    —N(R_(b))S(O)₂R_(a), —N(R_(b))alkylN(R_(b))S(O)₂R_(a),    —N(R_(b))alkylN(R_(b))C(O)OR_(a),    —N(R_(b))alkylN(R_(b))C(O)NR_(a)R_(b), -alkylSR_(a), -alkylS(O)R_(a)    or -alkylS(O)₂R_(a);-   R¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,    heterocycle, aryl or heteroaryl; wherein each R¹ is substituted with    0, 1 or 2 substituents independently selected from the group    consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl,    hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),    —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂, and    R^(1a);-   R^(1a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(1a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R² is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,    heterocycle, aryl or heteroaryl; wherein each R² is substituted with    0, 1 or 2 substituents independently selected from the group    consisting of halo, —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a),    —NR_(a)R_(b), —NR_(b)C(O)R_(a)—N(R_(b))C(O)OR_(a),    —N(R_(a))C(═N)NR_(a)R_(b), —N(R_(a))C(O)NR_(a)R_(b),    —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(2a);-   R^(2a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(2a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNR₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R³ is alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, -alkylOR_(a),    -alkylSR_(a), -alkylSOR_(a), -alkylSO₂R_(a), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)OR_(a),    -alkylN(R_(a))C(═N)NR_(a)R_(b), -alkylN(R_(a))C(O)NR_(a)R_(b),    -alkylC(O)NR_(a)R_(b), -alkylC(O)OR_(a), cycloalkyl,    cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle,    heterocyclealkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;    wherein the cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl,    cycloalkyl moiety of the cycloalkylalkyl, cycloalkenyl moiety of the    cycloalkenylalkyl, heterocycle moiety of the heterocyclealkyl,    heteroaryl moiety of the heteroarylalkyl and the aryl moiety of the    arylalkyl are independently substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and    R^(3a);-   R^(3a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(3a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    oxo, alkyl, alkenyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), and -alkylC(O)N(alkyl)₂;-   R⁴ is H and R⁵ is OR¹⁶; or-   R⁵ is H and R⁴ is OR⁶; or-   R⁴ and R⁵ are —OR¹⁶;    -   R⁶ is alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,        -alkylOR_(a), -alkylSR_(a), -alkylSOR_(a), -alkylSO₂R_(a),        -alkylNR_(a)R_(b), -alkylN(R_(b))C(O)R_(a),        -alkylN(R_(b))C(O)OR_(a), -alkylN(R_(a))C(═N)NR_(a)R_(b),        -alkylN(R_(a))C(O)NR_(a)R_(b), -alkylC(O)NR_(a)R_(b),        -alkylC(O)OR_(a), cycloalkyl, cycloalkylalkyl, cycloalkenyl,        cycloalkenylalkyl, heterocycle, heterocyclealkyl, aryl,        arylalkyl, heteroaryl or heteroarylalkyl; wherein the        cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl,        cycloalkyl moiety of the cycloalkylalkyl, cycloalkenyl moiety of        the cycloalkenylalkyl, heterocycle moiety of the        heterocyclealkyl, heteroaryl moiety of the heteroarylalkyl and        the aryl moiety of the arylalkyl are independently substituted        with 0, 1, 2, 3 or 4 substituents independently selected from        the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl,        alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH,        —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl,        —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH,        —C(O)Oalkyl, —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂,        haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH₂,        -alkylN(H)(alkyl), -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂,        -alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl)₂,        -alkylC(O)OH, -alkylC(O)Oalkyl, -alkylC(O)NH₂,        -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and R^(6a);-   R^(6a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(6a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    oxo, alkyl, alkenyl, hydroxy, alkoxy, —NH₂, N(H)(alkyl), —N(alkyl)₂,    —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl,    —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH,    —C(O)Oalkyl, —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), and -alkylC(O)N(alkyl)₂;-   R⁷ is —N(R_(b))C(O)OR_(a), alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, heterocycle, aryl or heteroaryl; wherein the alkyl,    alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl and    heteroaryl are independently substituted with 0, 1 or 2 substituents    independently selected from the group consisting of halo, —OR_(a),    OC(O)R_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —NR_(a)R_(b),    —N(R_(b))C(O)R_(a), —N(R_(b))C(O)OR_(a), —N(R_(a))C(═N)NR_(a)R_(b),    —N(R_(a))C(O)NR_(a)R_(b), —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(7a);-   R^(7a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(7a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R⁸ is —OR_(a), —NR_(a)R_(b), —N(R_(b))C(O)OR_(a), -alkylOR_(a),    -alkylOC(O)R_(a), or —O-alkylC(O)R_(a);-   R⁹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R⁹ is substituted with 0, 1,    2 or 3 substituents independently selected from the group consisting    of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro, oxo,    —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))SO₂R_(a),    —N(R_(b))SO₂NR_(a)R_(b), —N(R_(b))C(O)NR_(a)R_(b),    —N(R_(b))C(O)OR_(a), —C(O)R_(a), —C(O)NR_(a)R_(b), —C(O)OR_(a),    haloalkyl, nitroalkyl, cynaoalkyl, formylalkyl, -alkylOR_(a),    -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)OR_(a), -alkylN(R_(b))SO₂NR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkylC(O)R_(a),    -alkylC(O)NR_(a)R_(b) and R^(9a);-   R^(9a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(9a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹⁰ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R¹⁰ is substituted with 0,    1, 2 or 3 substituents independently selected from the group    consisting of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro,    oxo, —OR_(a), —SR_(a), —SOR_(a), SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))SO₂R_(a),    —N(R_(b))SO₂NR_(a)R_(b), —N(R_(b))C(O)NR_(a)R_(b),    —N(R_(b))C(O)OR_(a), —C(O)R_(a), —C(O)NR_(a)R_(b), —C(O)OR_(a),    haloalkyl, nitroalkyl, cynaoalkyl, formylalkyl, -alkylOR_(a),    -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)OR_(a), -alkylN(R_(b))SO₂NR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkylC(O)R_(a),    -alkylC(O)NR_(a)R_(b) and R^(10a);-   R^(10a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or    heteroaryl; wherein each R^(10a) is substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R¹¹ is substituted with 0,    1, 2 or 3 substituents independently selected from the group    consisting of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro,    oxo, —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))SO₂R_(a),    —N(R_(b))SO₂NR_(a)R_(b), —N(R_(b))C(O)NR_(a)R_(b),    —N(R_(b))C(O)OR_(a), —C(O)R_(a), —C(O)NR_(a)R_(b), —C(O)OR_(a),    haloalkyl, nitroalkyl, cynaoalkyl, formylalkyl, -alkylOR_(a),    -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)OR_(a), -alkylN(R_(b))SO₂NR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkylC(O)R_(a),    -alkylC(O)NR_(a)R_(b) and R^(11a);-   R^(11a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or    heteroaryl; wherein each R^(11a) is substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R¹² is alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl or    cycloalkenylalkyl; wherein each R¹² is substituted with 0, 1 or 2    substituents independently selected from the group consisting of    hydroxy, alkoxy and halo;-   R¹³ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R¹³ is substituted with 0,    1, 2 or 3 substituents independently selected from the group    consisting of alkyl, alkenyl, alkynyl, cyano, halo, nitro, oxo,    —OR_(a), —SR_(a), —SO_(a), —SO₂R_(a), —SO₂NR_(a), SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))C(O)OR_(a, —C(O)NR)    _(a)R_(b), —C(O)OR_(a), haloalkyl, nitroalkyl, cynaoalkyl,    -alkylOR_(a), -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)O_(a), -alkyl-C(O)NR_(a)R_(b) and    R^(13a);-   R^(13a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or    heteroaryl; wherein each R^(13a) is substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹⁴ is —OR_(a), -alkylOR_(a), aryl, heteroaryl or heterocycle;    wherein the aryl, heteroaryl and heterocycle are independently    substituted with 0, 1, 2, 3 or 4 substituents independently selected    from the group consisting of cyano, halo, nitro, oxo, alkyl,    alkenyl, alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂,    —SH, —S(alkyl), —SO₂(alkyl), —S(O)₂NR_(a)R_(b), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹⁶ is hydrogen or R¹⁵;-   R¹⁵ is

-   R₁₀₃ is C(R₁₀₅)₂, O or —N(R₁₀₅);-   R₁₀₄ is hydrogen, alkyl, haloalkyl, alkoxycarbonyl, aminocarbonyl,    alkylaminocarbonyl or dialkylaminocarbonyl,-   each M is independently selected from the group consisting of H,    —N(R₁₀₅)₂, alkyl, alkenyl, and R₁₀₆; wherein 1 to 4 —CH₂ radicals of    the alkyl or alkenyl, other than the —CH₂ radical that is bound to    Z, is optionally replaced by a heteroatom group selected from the    group consisting of O, S, S(O), SO₂ and N(R₁₀₅); and wherein any    hydrogen in said alkyl, alkenyl or R₁₀₆ is optionally replaced with    a substituent selected from the group consisting of oxo, —OR₁₀₅,    —R₁₀₅, —N(R₁₀₅)₂, —CN, —C(O)OR₁₀₅, —C(O)N(R₁₀₅)₂, —SO₂N(R₁₀₅),    —N(R₁₀₅)C(O)R₁₀₅, —C(O)R₁₀₅, —SR₁₀₅, —S(O)R₁₀₅, —SO₂R₁₀₅, —OCF₃,    —SR₁₀₆, —SOR₁₀₆, —SO₂R₁₀₆, —N(R₁₀₅)SO₂R₁₀₅, halo, —CF₃, NO₂ and    phenyl; provided that when M is —N(R₁₀₅)₂, Z₁ and Z₂ are —CH₂;-   Z₁ is CH₂, O, S, —N(R₁₀₅), or, when M is absent, H;-   Z₂ is CH₂, O, S or —N(R₁₀₅);-   Q is O or S;-   W is P or S; wherein when W is S, Z₁ and Z₂ are not S;-   M′ is H, alkyl, alkenyl or R₁₀₆; wherein 1 to 4 —CH₂ radicals of the    alkyl or alkenyl is optionally replaced by a heteroatom group    selected from O, S, S(O), SO₂, or N(R₁₀₅); and wherein any hydrogen    in said alkyl, alkenyl or R₁₀₆ is optionally replaced with a    substituent selected from the group consisting of oxo, —OR₁₀₅,    —R₁₀₅, —N(R₁₀₅)₂, —CN, —C(O)OR₁₀₅, —C(O)N(R₁₀₅)₂, —SO₂N(R₁₀₅),    —N(R₁₀₅)C(O)R₁₀₅, —C(O)R₁₀₅, —SR₁₀₅, —S(O)R₁₀₅, —SO₂R₁₀₅, —OCF₃,    —SR₁₀, —SOR₁₀₆, —N(R₁₀₅)SO₂R₁₀₅, halo, —CF₃ and NO₂;-   R₁₀₆ is a monocyclic or bicyclic ring system selected from the group    consisting of aryl, cycloalkyl, cycloalkenyl heteroaryl and    heterocycle; wherein any of said heteroaryl and heterocycle ring    systems contains one or more heteroatoms selected from the group    consisting of O, N, S, SO, SO₂ and N(R₁₀₅); and wherein any of said    ring system is substituted with 0, 1, 2, 3, 4, 5 or 6 substituents    selected from the group consisting of hydroxy, alkyl, alkoxy, and    —OC(O)alkyl;-   each R₁₀₅ is independently selected from the group consisting of H    or alkyl; wherein said alkyl is optionally substituted with a ring    system selected from the group consisting of aryl, cycloalkyl,    cycloalkenyl, heteroaryl and heterocycle; wherein any of said    heteroaryl and heterocycle ring systems contains one or more    heteroatoms selected from the group consisting of O, N, S, SO, SO₂,    and N(R₁₀₅); and wherein any one of said ring systems is substituted    with 0, 1, 2, 3 or 4 substituents selected from the group consisting    of oxo, —OR₁₀₅, —R₁₀₅, —N(R₁₀₅)₂, —N(R₁₀₅)C(O)R₁₀₅, —CN, —C(O)OR₁₀₅,    —C(O)N(R₁₀₅)₂, halo and —CF₃;-   each R₁₀₇ and R₁₀₈ are independently selected from the group    consisting of hydrogen and alkyl;-   q is 0 or 1;-   m is 0 or 1;-   m′ is 0 or 1;-   m″is 0 or 1;-   r is 0, 1, 2, 3 or 4;-   t is 0 or 1;-   R_(a) and R_(b) at each occurrence are independently selected from    the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    cycloalkyl, aryl, heteroaryl and heterocycle; wherein each R_(a) and    R_(b), at each occurrence, is independently substituted with 0, 1, 2    or 3 substituents independently selected from the group consisting    of cyano, nitro, halo, oxo, alkyl, alkenyl, alkynyl, hydroxy,    alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and R_(c);    alternatively, R_(a) and R_(b), together with the nitrogen atom to    which they are attached, form a ring selected from the group    consisting of heteroaryl and heterocycle; wherein each of the    heteroaryl and heterocycle is independently substituted with 0, 1, 2    or 3 substituents independently selected from the group consisting    of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo,    hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl), —SH, —S(alkyl),    —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, formylalkyl,    nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH₂,    -alkylN(H)(alkyl), -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂,    -alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH,    -alkylC(O)Oalkyl, -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl),    -alkylC(O)N(alkyl)₂ and R_(c);-   R_(c) is aryl, heteroaryl or heterocycle; wherein each R_(c) is    independently substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of halo, nitro,    oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkyl-NH₂, -alkyl-N(H)(alkyl), -alkyl-N(alkyl)₂,    -alkyl-N(H)C(O)NH₂, -alkyl-N(H)C(O)N(H)(alkyl),    -alkyl-N(H)C(O)N(alkyl)₂, -alkyl-C(O)OH, -alkyl-C(O)Oalkyl,    -alkyl-C(O)NH₂, -alkyl-C(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂; and    n is 1 or 2.

For example, the present invention provides a compound of formula (VIII)wherein X is O; Y is O and L, B, R^(A), R¹, R^(1a), R², R^(2a), R³,R^(3a), R⁴, R⁵, R⁶, R^(6a), R⁷, R^(7a), R⁸, R⁹, R¹⁰, R^(10a), R¹¹,R^(11a), R¹², R^(12a), R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M,Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b),R_(c), and n are defined in formula (VIII).

For example, the present invention provides a compound of formula (VIII)wherein X is O, Y is O, R⁴ is H, R⁵ is OR¹⁶; R² is alkyl; and L, B,R^(A), R¹, R^(1a), R³, R^(3a), R⁶, R^(6a), R⁷, R^(7a), R⁸, R⁹, R^(9a),R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R^(12a), R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶,R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r,t, R_(a), R_(b), R_(c), and n are defined in formula (VIII).

For example, the present invention provides a compound of formula (VIII)wherein X is O, Y is O, R⁴ is H, R⁵ is OR¹⁶, R² is alkyl, R³ isarylalkyl; and L, B, R^(A), R¹, R^(1a), R^(3a), R⁶, R^(6a), R⁷, R^(7a),R⁸, R⁹, R^(9a), R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R^(12a), R¹³, R^(13a),R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈,q, m, m′, m″, r, t, R_(a), R_(b), R_(c), and n are defined in formula(VIII).

For example, the present invention provides a compound of formula (VIII)wherein X is O, Y is O, R⁴ is H, R⁵ is OR¹⁶, R² is alkyl, R³ isarylalkyl substituted with 0 or one R^(3a); and L, B, R^(A), R¹, R^(1a),R^(3a), R⁶, R^(6a), R⁷, R^(7a), R⁸, R⁹, R^(9a), R¹⁰, R^(10a), R¹¹,R^(11a), R¹², R^(12a), R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M,Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a)R_(b),R_(c), and defined in formula (VIII).

For example, the present invention provides a compound of formula (VIII)wherein X is O, Y is O, R⁴ is H, R⁵ is OR¹⁶, R² is alkyl, R¹ isarylalkyl substituted with 0 or one R^(3a) is aryl or heteroaryl; and L,B, R^(A), R¹, R^(1a), R^(3a), R⁶, R_(6a), R⁷, R^(7a), R⁸, R⁹, R^(9a),R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R^(12a), R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶,R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″,r, t, R_(a), R_(b), R_(c), n and the substituents of R^(3a) are definedin formula (VIII).

For example, the present invention provides a compound of formula (VIII)wherein X is O, Y is O, R⁴ is H, R⁵ is OR¹⁶, R² is alkyl, R³ isarylalkyl substituted with 0 or one R^(3a), wherein, R^(3a) is aryl orheteroaryl, R¹ is alkyl; and L, B, R^(A), R⁶, R^(6a), R⁷, R^(7a), R⁸,R⁹, R^(9a), R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R^(12a), R¹³, R^(13a), R¹⁴,R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m,m′, m″, r, t, R_(a), R_(b), R_(c), n and the substituents of R^(3a) aredefined in formula (VIII).

For example, the present invention provides a compound of formula (VIII)wherein X is O, Y is O, R⁴ is H, R⁵ is OR¹⁶, R² is alkyl, R³ isarylalkyl substituted with 0 or one R^(3a) wherein R^(3a) is aryl orheteroaryl, R¹ is alkyl, and R⁶ is arylalkyl substituted with 0 or oneR^(6a) wherein R^(6a) is aryl or heteroaryl; and L, B, R^(A), R⁷,R^(7a), R⁸, R⁹, R^(9a), R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R^(12a), R¹³,R^(13a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆,R₁₀₇, R₁₀₈, q, m, m′, m″, r, n and the substituents of R^(3a) and R^(6a)are defined in formula (VIII).

For example, the present invention provides a compound of formula (VIII)wherein X is O, Y is O, R⁴ is H, R⁵ is OR¹⁶, R² is alkyl, R¹ is alkyl,each R₁₀₄ is independently hydrogen or alkyl, each R₁₀₅ is independentlyhydrogen or alkyl, each M is independently hydrogen or alkyl, Z₁ and Z₂are is O, Q is O, W is P, R⁶ is arylalkyl substituted with 0 or oneR^(6a) wherein R^(6a) is aryl or heteroaryl, R³ is arylalkyl substitutedwith R^(3a) wherein R^(3a) is aryl or heteroaryl; and L, B, R^(A), R⁷,R^(7a), R⁸, R⁹, R^(9a), R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R^(12a), R¹³,R^(13a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t,R_(a), R_(b), R_(c), n and the substituents of R^(3a) and R^(6a) aredefined in formula (VIII).

In a ninth embodiment the present invention provides a compound offormula (IX)

or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, wherein:

-   A is

-   X is O, S or NH;-   Y is O, S or NH;-   B is H or —CH₂R⁹;-   L is —C(═O), —C(═S), —C(═NH) or —S(O)₂;-   R^(A) is —N(H)C(O)R⁸, —O(R_(a)), —OC(O)OR_(a), —NR_(a)R_(b),    —N(R_(b))S(O)₂R_(a), —N(R_(b))alkylN(R_(b))S(O)₂R_(a),    —N(R_(b))alkylN(R_(b))C(O)OR_(a),    —N(R_(b))alkylN(R_(b))C(O)NR_(a)R_(b), -alkylSR_(a), -alkylS(O)R_(a)    or —alkylS(O)₂R_(a);-   R¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,    heterocycle, aryl or heteroaryl; wherein each R¹ is substituted with    0, 1 or 2 substituents independently selected from the group    consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl,    hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),    —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂, and    R^(1a);-   R^(1a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(1a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R² is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,    heterocycle, aryl or heteroaryl; wherein each R² is substituted with    0, 1 or 2 substituents independently selected from the group    consisting of halo, —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a),    —NR_(a)R_(b), —NR_(b)C(O)R_(a), —N(R_(b))C(O)OR_(a),    —N(R_(a))C(═N)NR_(a)R_(b), —N(R_(a))C(O)NR_(a)R_(b),    —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(2a);-   R^(2a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(2a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R³ is alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, -alkylOR_(a),    -alkylSR_(a), -alkylSOR_(a), -alkylSO₂R_(a), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)OR_(a),    -alkylN(R_(a))C(═N)NR_(a)R_(b), -alkylN(R_(a))C(O)NR_(a)R_(b),    -alkylC(O)NR_(a)R_(b), -alkylC(O)OR_(a), cycloalkyl,    cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle,    heterocyclealkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;    wherein the cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl,    cycloalkyl moiety of the cycloalkylalkyl, cycloalkenyl moiety of the    cycloalkenylalkyl, heterocycle moiety of the heterocyclealkyl,    heteroaryl moiety of the heteroarylalkyl and the aryl moiety of the    arylalkyl are independently substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and    R^(3a);-   R^(3a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(3a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    oxo, alkyl, alkenyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), and -alkylC(O)N(alkyl)₂;-   R⁴ is H and R⁵ is OR⁶; or-   R⁵ is H and R⁴ is OR¹⁶; or-   R⁴ and R⁵ are —OR¹⁶;-   R⁶ is alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, -alkylOR_(a),    -alkylSR_(a), -alkylSOR_(a), -alkylSO₂R_(a), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)OR_(a),    -alkylN(R_(a))C(═N)NR_(a)R_(b), -alkylN(R_(a))C(O)NR_(a)R_(b),    -alkylC(O)NR_(a)R_(b), -alkylC(O)OR_(a), cycloalkyl,    cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle,    heterocyclealkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;    wherein the cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl,    cycloalkyl moiety of the cycloalkylalkyl, cycloalkenyl moiety of the    cycloalkenylalkyl, heterocycle moiety of the heterocyclealkyl,    heteroaryl moiety of the heteroarylalkyl and the aryl moiety of the    arylalkyl are independently substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and    R^(6a);-   R^(6a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(6a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    oxo, alkyl, alkenyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), and -alkylC(O)N(alkyl)₂;-   R⁷ is —N(R_(b))C(O)OR_(a), alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, heterocycle, aryl or heteroaryl; wherein the alkyl,    alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl and    heteroaryl are independently substituted with 0, 1 or 2 substituents    independently selected from the group consisting of halo, —OR_(a),    —OC(O)R_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —NR_(a)R_(b),    —N(R_(b))C(O)R_(a), —N(R_(b))C(O)OR_(a), —N(R_(a))C(═N)NR_(a)R_(b),    —N(R_(a))C(O)NR_(a)R_(b), —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(7a);-   R^(7a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(7a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R⁸ is —OR_(a), —NR_(a)R_(b), —N(R_(b))C(O)OR_(a), -alkylOR_(a),    -alkylOC(O)R_(a), or -alkylC(O)R_(a);-   R⁹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R⁹ is substituted with 0, 1,    2 or 3 substituents independently selected from the group consisting    of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro, oxo,    —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))SO₂R_(a),    —N(R_(b))SO₂NR_(a)R_(b), —N(R_(b))C(O)NR_(a)R_(b),    —N(R_(b))C(O)OR_(a), —C(O)R_(a), —C(O)NR_(a)R_(b), —C(O)OR_(a),    haloalkyl, nitroalkyl, cynaoalkyl, formylalkyl, -alkylOR_(a),    -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)OR_(a), -alkylN(R_(b))SO₂NR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkylC(O)R_(a),    -alkylC(O)NR_(a)R_(b) and R^(9a);-   R^(9a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(9a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹⁰ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R¹⁰ is substituted with 0,    1, 2 or 3 substituents independently selected from the group    consisting of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro,    oxo, —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))SO₂R_(a),    —N(R_(b))SO₂NR_(a)R_(b), —N(R_(b))C(O)NR_(a)R_(b),    —N(R_(b))C(O)OR_(a), —C(O)R_(a), —C(O)NR_(a)R_(b), —C(O)OR_(a),    haloalkyl, nitroalkyl, cynaoalkyl, formylalkyl, -alkylOR_(a),    -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)OR_(a), -alkylN(R_(b))SO₂NR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkylC(O)R_(a),    -alkylC(O)NR_(a)R_(b) and R^(10a);-   R^(10a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or    heteroaryl; wherein each R^(10a) is substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R¹¹ is substituted with 0,    1, 2 or 3 substituents independently selected from the group    consisting of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro,    oxo, —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))SO₂R_(a),    —N(R_(b))SO₂NR_(a)R_(b), —N(R_(b))C(O)NR_(a)R_(b),    —N(R_(b))C(O)OR_(a), —C(O)R_(a), —C(O)NR_(a)R_(b), —C(O)OR_(a),    haloalkyl, nitroalkyl, cynaoalkyl, formylalkyl, -alkylOR_(a),    -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)OR_(a), -alkylN(R_(b))SO₂NR_(a)R_(b),    -alkylN(R_(b))C(O)R, -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkylC(O)R_(a),    -alkylC(O)NR_(a)R_(b) and R^(11a);-   R^(11a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or    heteroaryl; wherein each R^(11a) is substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R¹² is alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl or    cycloalkenylalkyl; wherein each R¹² is substituted with 0, 1 or 2    substituents independently selected from the group consisting of    hydroxy, alkoxy and halo;-   R¹³ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R¹³ is substituted with 0,    1, 2 or 3 substituents independently selected from the group    consisting of alkyl, alkenyl, alkynyl, cyano, halo, nitro, oxo,    —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))C(O)OR_(a),    —C(O)NR_(a)R_(b), —C(O)OR_(a), haloalkyl, nitroalkyl, cynaoalkyl,    -alkylOR_(a), -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkyl-C(O)NR_(a)R_(b) and    R^(13a);-   R^(13a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or    heteroaryl; wherein each R^(13a) is substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹⁴ is —OR_(a), -alkylOR_(a), aryl, heteroaryl or heterocycle;    wherein the aryl, heteroaryl and heterocycle are independently    substituted with 0, 1, 2, 3 or 4 substituents independently selected    from the group consisting of cyano, halo, nitro, oxo, alkyl,    alkenyl, alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂,    —SH, —S(alkyl), —SO₂(alkyl), —S(O)₂NR_(a)R_(b), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹⁶ is hydrogen or R¹⁵;-   R¹⁵ is

-   R₁₀₃ is C(R₁₀₅)₂, O or —N(R₁₀₅);-   R₁₀₄ is hydrogen, alkyl, haloalkyl, alkoxycarbonyl, aminocarbonyl,    alkylaminocarbonyl or dialkylaminocarbonyl,-   each M is independently selected from the group consisting of H,    —N(R₁₀₅)₂, alkyl, alkenyl, and R₁₀₆; wherein 1 to 4 —CH₂ radicals of    the alkyl or alkenyl, other than the —CH₂ radical that is bound to    Z, is optionally replaced by a heteroatom group selected from the    group consisting of O, S, S(O), SO₂ and N(R₁₀₅); and wherein any    hydrogen in said alkyl, alkenyl or R₁₀₆ is optionally replaced with    a substituent selected from the group consisting of oxo, —OR₁₀₅,    —R₁₀₅, —N(R₁₀₅)₂, —CN, —C(O)OR₁₀₅, —C(O)N(R₁₀₅)₂, —SO₂N(R₁₀₅),    —N(R₁₀₅)C(O)R₁₀₅, —C(O)R₁₀₅, —SR₁₀₅, —S(O)R₁₀₅, —SO₂R₁₀₅, —OCF₃,    —SR₁₀₆, —SOR₁₀₆, —SO₂R₁₀₆, —N(R₁₀₅)SO₂R₁₀₅, halo, —CF₃, NO₂ and    phenyl; provided that when M is —N(R₁₀₅)₂, Z₁ and Z₂ are —CH₂;-   Z₁ is CH₂, O, S, N(R₁₀₅), or, when M is absent, H;-   Z₂ is CH₂, O, S or —N(R₁₀₅);-   Q is O or S;-   W is P or S; wherein when W is S, Z₁ and Z₂ are not S;-   M′ is H, alkyl, alkenyl or R₁₀₆; wherein 1 to 4 —CH₂ radicals of the    alkyl or alkenyl is optionally replaced by a heteroatom group    selected from O, S, S(O), SO₂, or N(R₁₀₅); and wherein any hydrogen    in said alkyl, alkenyl or R₁₀₆ is optionally replaced with a    substituent selected from the group consisting of oxo, —OR₁₀₅,    —R₁₀₅, —N(R₁₀₅)₂, —CN, —C(O)OR₁₀₅, —C(O)N(R₁₀₅)₂, —SO₂N(R₁₀₅),    —N(R₁₀₅)C(O)R₁₀₅, —C(O)R₁₀₅, —SR₁₀₅, —S(O)R₁₀₅, —SO₂R₁₀₅, —OCF₃,    —SR₁₀₆, —SOR₁₀₆, —SO₂R₁₀₆, —N(R₁₀₅)SO₂R₁₀₅, halo, —CF₃ and NO₂;-   R₁₀₆ is a monocyclic or bicyclic ring system selected from the group    consisting of aryl, cycloalkyl, cycloalkenyl heteroaryl and    heterocycle; wherein any of said heteroaryl and heterocycle ring    systems contains one or more heteroatoms selected from the group    consisting of O, N, S, SO, SO₂ and N(R₁₀₅); and wherein any of said    ring system is substituted with 0, 1, 2, 3, 4, 5 or 6 substituents    selected from the group consisting of hydroxy, alkyl, alkoxy, and    —OC(O)alkyl;-   each R₁₀₅ is independently selected from the group consisting of H    or alkyl; wherein said alkyl is optionally substituted with a ring    system selected from the group consisting of aryl, cycloalkyl,    cycloalkenyl, heteroaryl and heterocycle; wherein any of said    heteroaryl and heterocycle ring systems contains one or more    heteroatoms selected from the group consisting of O, N, S, SO, SO₂,    and N(R₁₀₅); and wherein any one of said ring systems is substituted    with 0, 1, 2, 3 or 4 substituents selected from the group consisting    of oxo, —OR₁₀₅, —R₁₀₅, —N(R₁₀₅)₂, —N(R₁₀₅)C(O)R₁₀₅, —CN, —C(O)OR₁₀₅,    —C(O)N(R₁₀₅)₂, halo and —CF₃;-   each R₁₀₇ and R₁₀₈ are independently selected from the group    consisting of hydrogen and alkyl;-   q is 0 or 1;-   m is 0 or 1;-   m′ is 0 or 1;-   m″ is 0 or 1;-   r is 0, 1, 2, 3 or 4;-   t is 0 or 1;-   R_(a) and R_(b) at each occurrence are independently selected from    the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    cycloalkyl, aryl, heteroaryl and heterocycle; wherein each R_(a) and    R_(b), at each occurrence, is independently substituted with 0, 1, 2    or 3 substituents independently selected from the group consisting    of cyano, nitro, halo, oxo, alkyl, alkenyl, alkynyl, hydroxy,    alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl), —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and R_(c);-   alternatively, R_(a) and R_(b), together with the nitrogen atom to    which they are attached, form a ring selected from the group    consisting of heteroaryl and heterocycle; wherein each of the    heteroaryl and heterocycle is independently substituted with 0, 1, 2    or 3 substituents independently selected from the group consisting    of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo,    hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),    —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, formylalkyl,    nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH₂,    -alkylN(H)(alkyl), -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂,    -alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH,    -alkylC(O)Oalkyl, -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl),    -alkylC(O)N(alkyl)₂ and R_(c);-   R_(c) is aryl, heteroaryl or heterocycle; wherein each R_(c) is    independently substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of halo, nitro,    oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkyl-NH₂, -alkyl-N(H)(alkyl), -alkyl-N(alkyl)₂,    -alkyl-N(H)C(O)NH₂, -alkyl-N(H)C(O)N(H)(alkyl),    -alkyl-N(H)C(O)N(alkyl)₂, -alkyl-C(O)OH, -alkyl-C(O)Oalkyl,    -alkyl-C(O)NH₂, -alkyl-C(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂; and    n is 1 or 2.

For example, the present invention provides a compound of formula (IX)wherein L is —C(═O) or —C(═S), X is O; Y is O; and L, B, R^(A), R¹,R^(1a), R², R^(2a), R³, R^(3a), R⁴, R⁵, R⁶, R^(6a), R⁷, R^(7a), R⁸, R⁹,R^(9a), R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R^(12a), R¹³, R^(13a), R¹⁴,R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m,m′, m″, r, t, R_(a), R_(b), R_(c), and n are defined in formula (IX).

For example, the present invention provides a compound of formula (IX)wherein X is O, Y is O, R⁴ is H, R⁵is OR¹⁶, R² is alkyl; and L, B,R^(A), R¹, R^(1a), R³, R^(3a), R⁶, R^(6a), R⁷, R^(7a), R⁸, R⁹, R^(9a),R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R^(12a), R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶,R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″,r, t, R_(a), R_(b), R_(c), and n are defined in formula (IX).

For example, the present invention provides a compound of formula (IX)wherein X is O, Y is O, R⁴ is H, R⁵ is OR¹⁶, R²is alkyl, R³ isarylalkyl; and L, B, R^(A), R¹, R^(1a), R^(3a), R⁶, R^(6a), R⁷, R^(7a),R⁸, R⁹, R^(9a), R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R^(12a), R¹³, R^(13a),R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈,q, m, m′, m″, r, t, R_(a), R_(b), R_(c), n and the substituents of thearyl moiety of arylalkyl of R³ are defined in formula (IX).

For example, the present invention provides a compound of formula (IX)wherein X is O, Y is O, R⁴ is H, R⁵ is OR¹⁶, R² is alkyl and R³ isarylalkyl wherein the aryl moiety of the arylalkyl is substituted with 0or one R^(3a); and L, B, R^(A), R¹, R^(1a), R³, R^(3a), R⁶, R^(6a), R⁷,R^(7a), R⁸, R⁹, R^(9a), R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R^(12a), R¹³,R^(13a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆,R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c), and n are definedin formula (IX).

For example, the present invention provides a compound of formula (IX)wherein X is O, Y is O, R⁴ is H, R⁵ is OR¹⁶, R² is alkyl, R³ isarylalkyl wherein the aryl moiety of the arylalkyl is substituted with 0or one R^(3a) wherein R^(3a) is aryl or heteroaryl; and L, B, R^(A), R¹,R^(1a), R⁶, R^(6a), R⁷, R^(7a), R⁸, R⁹, R^(9a), R¹⁰, R^(10a), R¹¹,R^(11a), R¹², R^(12a), R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M,Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b),R_(c), n and the substituents of R^(3a) are defined in formula (IX).

For example, the present invention provides a compound of formula (IX)wherein X is O, Y is O, R⁴ is H, R⁵ is OR¹⁶, R² is alkyl, R¹ is alkyl,R³is arylalkyl wherein the aryl moiety of the arylalkyl is substitutedwith 0 or one R^(3a) wherein R^(3a) is aryl or heteroaryl; and L, B,R^(A), R⁶, R^(6a), R⁷, R^(7a), R⁸, R⁹, R^(9a), R¹⁰, R^(10a), R¹¹,R^(11a), R¹², R^(12a), R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M,Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b),R_(c), n and the substituents of R^(3a) are defined in formula (IX).

For example, the present invention provides a compound of formula (IX)wherein X is O, Y is O, R⁴ is H, R⁵ is OR¹⁶, R² is alkyl, R¹ is alkyl,R⁶is arylalkyl substituted with 0 or one R^(6a) wherein R^(6a) is arylor heteroaryl, and R³ is arylalkyl wherein the aryl moiety of thearylalkyl is substituted with 0 or one R^(3a) wherein R^(3a) is aryl orheteroaryl; and L, B, R^(A), R⁷, R^(7a), R⁸, R⁹, R^(9a), R¹⁰, R^(10a),R¹¹, R^(11a), R¹², R^(12a), R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶, R₁₀₄, R₁₀₅, M,Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b),R_(c), n and the substituents of R^(3a) and R^(6a) are defined informula (IX).

For example, the present invention provides a compound of formula (IX)wherein X is O, Y is O, R⁴ is H, R^(5 is OR) ¹⁶, R² is alkyl, R¹ isalkyl, each R₁₀₄ is independently hydrogen or alkyl, each R₁₀₅ isindependently hydrogen or alkyl, each M is independently hydrogen oralkyl, Z₁ and Z₂ are O, Q is O, W is P, R⁶ is arylalkyl substituted with0 or one R^(6a) wherein R^(6a) is aryl or heteroaryl, and R³ isarylalkyl wherein the aryl moiety of the arylalkyl is substituted with 0or one R^(3a) wherein R^(3a) is aryl or heteroaryl; and L, B, R^(A), R⁷,R^(7a), R⁸, R⁹, R^(9a, R) ¹⁰, R^(10a), R¹¹R^(11a), R¹², R^(12a), R¹³,R^(13a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t,R_(a), R_(b), R_(c), n and the substituents of R^(3a) and R^(6a) aredefined in formula (IX).

In a tenth embodiment, the present invention provides a compound offormula (X)

or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, wherein:

-   A is

-   X is O, S or NH;-   Y is O, S or NH;-   B is H or —CH₂R⁹;-   L is —C(═O), —C(═S), —C(═NH) or —S(O)₂;-   R^(A) is —N(H)C(O)R⁸, —O(R_(a)), —OC(O)OR_(a), —NR_(a)R_(b),    —N(R_(b))S(O)₂R_(a), —N(R_(b))alkylN(R_(b))S(O)₂R_(a),    —N(R_(b))alkylN(R_(b))C(O)OR_(a),    —N(R_(b))alkylN(R_(b))C(O)NR_(a)R_(b), -alkylSR_(a), -alkylS(O)R_(a)    or -alkylS(O)₂R_(a);-   R¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,    heterocycle, aryl or heteroaryl; wherein each R¹ is substituted with    0, 1 or 2 substituents independently selected from the group    consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl,    hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),    —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂, and    R^(1a);-   R^(1a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(1a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R² is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,    heterocycle, aryl or heteroaryl; wherein each R² is substituted with    0, 1 or 2 substituents independently selected from the group    consisting of halo, —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a),    —NR_(a)R_(b), —NR_(b)C(O)R_(a)—N(R_(b))C(O)OR_(a),    —N(R_(a))C(═N)NR_(a)R_(b), —N(R_(a))C(O)NR_(a)R_(b),    —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(2a);-   R^(2a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(2a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R³ is alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, -alkylOR_(a),    -alkylSR_(a), -alkylSOR_(a), -alkylSO₂R_(a), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)OR_(a),    -alkylN(R_(a))C(═N)NR_(a)R_(b), -alkylN(R_(a))C(O)NR_(a)R_(b),    -alkylC(O)NR_(a)R_(b), -alkylC(O)OR_(a), cycloalkyl,    cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle,    heterocyclealkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;    wherein the cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl,    cycloalkyl moiety of the cycloalkylalkyl, cycloalkenyl moiety of the    cycloalkenylalkyl, heterocycle moiety of the heterocyclealkyl,    heteroaryl moiety of the heteroarylalkyl and the aryl moiety of the    arylalkyl are independently substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and    R^(3a);-   R^(3a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(3a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    oxo, alkyl, alkenyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), and -alkylC(O)N(alkyl)₂;-   R⁴ is H and R⁵ is OR¹⁶; or-   R⁵ is H and R⁴ is OR¹⁶; or-   R⁴ and R⁵ are —OR¹⁶;-   R⁶ is alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, -alkylOR_(a),    -alkylSR_(a), -alkylSOR_(a), -alkylSO₂R_(a), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)OR_(a),    -alkylN(R_(a))C(═N)NR_(a)R_(b), -alkylN(R_(a))C(O)NR_(a)R_(b),    -alkylC(O)NR_(a)R_(b), -alkylC(O)OR_(a), cycloalkyl,    cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle,    heterocyclealkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;    wherein the cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl,    cycloalkyl moiety of the cycloalkylalkyl, cycloalkenyl moiety of the    cycloalkenylalkyl, heterocycle moiety of the heterocyclealkyl,    heteroaryl moiety of the heteroarylalkyl and the aryl moiety of the    arylalkyl are independently substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and    R^(6a);-   R^(6a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(6a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    oxo, alkyl, alkenyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), and -alkylC(O)N(alkyl)₂;-   R⁷ is —N(R_(b))C(O)OR_(a), alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, heterocycle, aryl or heteroaryl; wherein the alkyl,    alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl and    heteroaryl are independently substituted with 0, 1 or 2 substituents    independently selected from the group consisting of halo, —OR_(a),    —OC(O)R_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —NR_(a)R_(b),    —N(R_(b))C(O)R_(a), —N(R_(b))C(O)OR_(a), —N(R_(a))C(═N)NR_(a)R_(b),    —N(R_(a))C(O)NR_(a)R_(b), —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(7a);-   R^(7a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(7a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R⁸ is —OR_(a), —NR_(a)R_(b), —N(R_(b))C(O)OR_(a), -alkylOR_(a),    -alkylOC(O)R_(a), or —O-alkylC(O)R_(a);-   R⁹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R⁹ is substituted with 0, 1,    2 or 3 substituents independently selected from the group consisting    of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro, oxo,    —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))SO₂R_(a),    —N(R_(b))SO₂NR_(a)R_(b), —N(R_(b))C(O)NR_(a)R_(b),    —N(R_(b))C(O)OR_(a), —C(O)R_(a), —C(O)NR_(a)R_(b), —C(O)OR_(a),    haloalkyl, nitroalkyl, cynaoalkyl, formylalkyl, -alkylOR_(a),    -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)OR_(a), -alkylN(R_(b))SO₂NR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkylC(O)R_(a),    -alkylC(O)NR_(a)R_(b) and R^(9a);-   R^(9a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(9a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹⁰ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R¹⁰ is substituted with 0,    1, 2 or 3 substituents independently selected from the group    consisting of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro,    oxo, —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))SO₂R_(a),    —N(R_(b))SO₂NR_(a)R_(b), —N(R_(b))C(O)NR_(a)R_(b),    —N(R_(b))C(O)OR_(a), —C(O)R_(a), —C(O)NR_(a)R_(b), —C(O)OR_(a),    haloalkyl, nitroalkyl, cynaoalkyl, formylalkyl, -alkylOR_(a),    -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    alkylN(R_(b))C(O)OR_(a), -alkylN(R_(b))SO₂NR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkylC(O)R_(a),    -alkylC(O)NR_(a)R_(b) and R^(10a);-   R^(10a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or    heteroaryl; wherein each R^(10a) is substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R¹¹ is substituted with 0,    1, 2 or 3 substituents independently selected from the group    consisting of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro,    oxo, R_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))SO₂R_(a),    —N(R_(b))SO₂NR_(a)R_(b), —N(R_(b))C(O)NR_(a)R_(b),    —N(R_(b))C(O)OR_(a), —C(O)R_(a), —C(O)NR_(a)R_(b), —C(O)OR_(a),    haloalkyl, nitroalkyl, cynaoalkyl, formylalkyl, -alkylOR_(a),    -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)OR_(a), -alkylN(R_(b))SO₂NR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkylC(O)R_(a),    -alkylC(O)NR_(a)R_(b) and R^(11a);-   R^(11a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or    heteroaryl; wherein each R^(11a) is substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R¹² is alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl or    cycloalkenylalkyl; wherein each R¹² is substituted with 0, 1 or 2    substituents independently selected from the group consisting of    hydroxy, alkoxy and halo;-   R¹³ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R¹³ is substituted with 0,    1, 2 or 3 substituents independently selected from the group    consisting of alkyl, alkenyl, alkynyl, cyano, halo, nitro, oxo,    —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))C(O)OR_(a),    —C(O)NR_(a)R_(b), —C(O)OR_(a), haloalkyl, nitroalkyl, cynaoalkyl,    -alkylOR_(a), -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkyl-C(O)NR_(a)R_(b) and    R^(13a);-   R^(13a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or    heteroaryl; wherein each R^(13a) is substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹⁴ is —OR_(a), -alkylOR_(a), aryl, heteroaryl or heterocycle;    wherein the aryl, heteroaryl and heterocycle are independently    substituted with 0, 1, 2, 3 or 4 substituents independently selected    from the group consisting of cyano, halo, nitro, oxo, alkyl,    alkenyl, alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂,    —SH, —S(alkyl), —SO₂(alkyl), —S(O)₂NR_(a)R_(b), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹⁶ is hydrogen or R¹⁵;-   R¹⁵ is

-   R₁₀₃ is C(R₁₀₅)₂, O or —N(R₁₀₅);-   R₁₀₄ is hydrogen, alkyl, haloalkyl, alkoxycarbonyl, aminocarbonyl,    alkylaminocarbonyl or dialkylaminocarbonyl,-   each M is independently selected from the group consisting of H,    —N(R₁₀₅)₂, alkyl, alkenyl, and R₁₀₆; wherein 1 to 4 —CH₂ radicals of    the alkyl or alkenyl, other than the —CH₂ radical that is bound to    Z, is optionally replaced by a heteroatom group selected from the    group consisting of O, S, S(O), SO₂ and N(R₁₀₅); and wherein any    hydrogen in said alkyl, alkenyl or R₁₀₆ is optionally replaced with    a substituent selected from the group consisting of oxo, —OR₁₀₅,    —R₁₀₅, —N(R₁₀₅)₂, —CN, —C(O)OR₁₀₅, —C(O)N(R₁₀₅)₂, —SO₂N(R₁₀₅),    —N(R₁₀₅)C(O)R₁₀₅, —C(O)R₁₀₅, —SR₁₀₅, —S(O)R₁₀₅, —SO₂R₁₀₅, —OCF₃,    —SR₁₀₆, —SOR₁₀₆, —SO₂R₁₀₆, —N(R₁₀₅)SO₂R₁₀₅, halo, —CF₃, NO₂ and    phenyl; provided that when M is —N(R₁₀₅)₂, Z₁ and Z₂ are —CH₂;-   Z₁ is CH₂, O, S, —N(R₁₀₅), or, when M is absent, H;-   Z₂ is CH₂, O, S or —N(R₁₀₅);-   Q is O or S;-   W is P or S; wherein when W is S, Z₁ and Z₂ are not S;-   M′ is H, alkyl, alkenyl or R₁₀₆; wherein 1 to 4 —CH₂ radicals of the    alkyl or alkenyl is optionally replaced by a heteroatom group    selected from O, S, S(O), SO₂, or N(R₁₀₅); and wherein any hydrogen    in said alkyl, alkenyl or R₁₀₆ is optionally replaced with a    substituent selected from the group consisting of oxo, —OR₁₀₅,    —R₁₀₅, —N(R₁₀₅)₂, —CN, —C(O)OR₁₀₅, —C(O)N(R₁₀₅)₂, —SO₂N(R₁₀₅),    —N(R₁₀₅)C(O)R₁₀₅, —C(O)R₁₀₅, —SR₁₀₅, —S(O)R₁₀₅, —SO₂R₁₀₅, —OCF₃,    —SR₁₀₆, —SOR₁₀₆, —SO₂R₁₀₆, —N(R₁₀₅)SO₂R₁₀₅, halo, —CF₃ and NO₂;-   R₁₀₆ is a monocyclic or bicyclic ring system selected from the group    consisting of aryl, cycloalkyl, cycloalkenyl heteroaryl and    heterocycle; wherein any of said heteroaryl and heterocycle ring    systems contains one or more heteroatoms selected from the group    consisting of O, N, S, SO, SO₂ and N(R₁₀₅); and wherein any of said    ring system is substituted with 0, 1, 2, 3, 4, 5 or 6 substituents    selected from the group consisting of hydroxy, alkyl, alkoxy, and    —OC(O)alkyl;-   each R₁₀₅ is independently selected from the group consisting of H    or alkyl; wherein said alkyl is optionally substituted with a ring    system selected from the group consisting of aryl, cycloalkyl,    cycloalkenyl, heteroaryl and heterocycle; wherein any of said    heteroaryl and heterocycle ring systems contains one or more    heteroatoms selected from the group consisting of O, N, S, SO, SO₂,    and N(R₁₀₅); and wherein any one of said ring systems is substituted    with 0, 1, 2, 3 or 4 substituents selected from the group consisting    of oxo, —OR₁₀₅, —R₁₀₅, —N(R₁₀₅)₂, —N(R₁₀₅)C(O)R₁₀₅, —CN, —C(O)OR₁₀₅,    —C(O)N(R₁₀₅)₂, halo and —CF₃;-   each R₁₀₇ and R₁₀₈ are independently selected from the group    consisting of hydrogen and alkyl;-   q is 0 or 1;-   m is 0 or 1;-   m′ is 0 or 1;-   m″ is 0 or 1;-   r is 0, 1, 2, 3 or 4;-   t is 0 or 1;-   R_(a) and R_(b) at each occurrence are independently selected from    the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    cycloalkyl, aryl, heteroaryl and heterocycle; wherein each R_(a) and    R_(b), at each occurrence, is independently substituted with 0, 1, 2    or 3 substituents independently selected from the group consisting    of cyano, nitro, halo, oxo, alkyl, alkenyl, alkynyl, hydroxy,    alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl), —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and R_(c);-   alternatively, R_(a) and R_(b), together with the nitrogen atom to    which they are attached, form a ring selected from the group    consisting of heteroaryl and heterocycle; wherein each of the    heteroaryl and heterocycle is independently substituted with 0, 1, 2    or 3 substituents independently selected from the group consisting    of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo,    hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),    —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, formylalkyl,    nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH₂,    -alkylN(H)(alkyl), -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂,    -alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH,    -alkylC(O)Oalkyl, -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl),    -alkylC(O)N(alkyl)₂ and R_(c);-   R_(c) is aryl, heteroaryl or heterocycle; wherein each R_(c) is    independently substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of halo, nitro,    oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkyl-NH₂, -alkyl-N(H)(alkyl), -alkyl-N(alkyl)₂,    -alkyl-N(H)C(O)NH₂, -alkyl-N(H)C(O)N(H)(alkyl),    -alkyl-N(H)C(O)N(alkyl)₂, -alkyl-C(O)OH, -alkyl-C(O)Oalkyl,    -alkyl-C(O)NH₂, -alkyl-C(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂; and    n is 1 or 2.

For example, the present invention provides a compound of formula (X)wherein L is —C(═O) or —C(═S), X is O; Y is O; and L, B, R^(A), R¹,R^(1a), R², R^(2a), R³, R^(3a), R⁴, R⁵, R⁶, R^(6a), R⁷, R^(7a), R⁸, R⁹,R^(9a), R¹⁰, R^(10a), R¹¹, R^(11a) , R¹², R^(12a), R¹³, R^(13a), R¹⁴,R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m,m′, m″, r, t, R_(a), R_(b), R_(c), and n are defined in formula (X).

For example, the present invention provides a compound of formula (X)wherein X is O, Y is O, R⁴ is H, R⁵ is OR¹⁶, R² is alkyl; and L, B,R^(A), R¹, R^(1a), R³, R^(3a), R⁶, R^(6a), R⁷, R^(7a), R⁸, R⁹, R^(9a),R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R^(12a), R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶,R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″,r, t, R_(a), R_(b), R_(c), and n are defined in formula (X).

For example, the present invention provides a compound of formula (X)wherein X is O, Y is O, R is H, R⁵ is OR¹⁶, R² is alkyl, R³ isarylalkyl; and L, B, R^(A), R¹, R^(1a), R^(3a), R⁶, R_(6a), R⁷, R^(7a),R⁸, R⁹, R^(9a), R¹⁰, R^(10a), R¹¹, R¹², R^(12a), R¹³, R^(13a), R¹⁴, R¹⁵,R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′,m″, r, t, R_(a), R_(b), R_(c), n and the substituents of the aryl moietyof arylalkyl of R³ are defined in formula (X).

For example, the present invention provides a compound of formula (X)wherein X is O, Y is O, R⁴ is H, R⁵ is OR¹⁶, R² is alkyl and R³ isarylalkyl wherein the aryl moiety of the arylalkyl is substituted with 0or one R^(3a); and L, B, R^(A), R¹, R^(1a), R_(3a), R⁶, R^(6a), R⁷,R^(7a), R⁸, R⁹, R^(9a), R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R^(12a), R¹³,R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈,q, m, m′, m″, r, t, R_(a), R_(b), R_(c), and n are defined in formula(X).

For example, the present invention provides a compound of formula (X)wherein X is O, Y is O, R⁴ is H, R⁵ is OR¹⁶, R² is alkyl, R³ isarylalkyl wherein the aryl moiety of the arylalkyl is substituted with 0or one R^(3a) wherein R^(3a) is aryl or heteroaryl; and L, B, R^(A), R¹,R^(1a), R⁶, R^(6a), R⁷, R^(7a), R⁸, R⁹, R^(9a), R¹⁰, R¹¹, R^(11a), R¹²,R^(12a), R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W,M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c), n and thesubstituents of R^(3a) are defined in formula (X).

For example, the present invention provides a compound of formula (IX)wherein X is O, Y is O, R⁴ is H, R⁵ is OR¹⁶, R² is alkyl, R¹ is alkyl,R³is arylalkyl wherein the aryl moiety of the arylalkyl is substitutedwith 0 or one R^(3a) wherein R^(3a) is aryl or heteroaryl; and L, B,R^(A), R⁶, R^(6a), R⁷, R^(7a), R⁸, R⁹, R^(9a), R¹⁰, R^(10a), R¹¹,R^(11a), R¹², R^(12a), R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M,Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b),R_(c), n and the substituents of R^(3a) are defined in formula (X).

For example, the present invention provides a compound of formula (X)wherein X is O, Y is O, R⁴ is H, R⁵ is OR¹⁶, R² is alkyl, R¹ is alkyl,R⁶is arylalkyl substituted with 0 or one R^(6a) wherein R^(6a) is arylor heteroaryl, and R³ is arylalkyl wherein the aryl moiety of thearylalkyl is substituted with 0 or one R^(3a) wherein R^(3a) is aryl orheteroaryl; and L, B, R^(A), R⁷, R^(7a), R⁸, R⁹, R^(9a), R¹⁰, R^(10a),R¹¹, R^(11a), R¹², R^(12a), R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄,R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a),R_(b), R_(c), n and the substituents of R^(3a) and R^(6a) are defined informula (X).

For example, the present invention provides a compound of formula (X)wherein X is O, Y is O, R⁴is H, R⁵ is OR¹⁶, R¹ is alkyl, R¹ is alkyl,each R₁₀₄ is independently hydrogen or alkyl, each R₁₀₅ is independentlyhydrogen or alkyl, each M is independently hydrogen or alkyl, Z₁ and Z₂are O, Q is O, W is P, R⁶ is arylalkyl substituted with 0 or one R^(6a)wherein R^(6a) is aryl or heteroaryl, and R³ is arylalkyl wherein thearyl moiety of the arylalkyl is substituted with 0 or one R^(3a) whereinR^(3a) is aryl or heteroaryl; and L, B, R^(A), R⁷, R^(7a), R⁸, R⁹,R^(9a), R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R^(12a), R¹³, R^(13a), R¹⁴,R¹⁵, R¹⁶, R₁₀₃, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b),R_(c), n and the substituents of R^(3a) and R^(6a) are defined informula (X).

In an eleventh embodiment, the present invention provides a compound offormula (XI)

or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, wherein:

-   A is

-   X is O, S or NH;-   Y is O, S or NH;-   B is H or —CH₂R⁹;-   L is —C(═O), —C(═S), —C(═NH) or —S(O)₂;-   R^(A) is —N(H)C(O)R⁸, —O(R_(a)), —OC(O)OR_(a), —NR_(a)R_(b),    —N(R_(b))S(O)₂R_(a), —N(R_(b))alkylN(R_(b))S(O)₂R_(a),    —N(R_(b))alkylN(R_(b))C(O)OR_(a),    —N(R_(b))alkylN(R_(b))C(O)NR_(a)R_(b), -alkylSR_(a), -alkylS(O)R_(a)    or -alkylS(O)₂R_(a);-   R¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,    heterocycle, aryl or heteroaryl; wherein each R¹ is substituted with    0, 1 or 2 substituents independently selected from the group    consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl,    hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),    —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂, and    R^(1a);-   R^(1a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(1a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R² is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,    heterocycle, aryl or heteroaryl; wherein each R² is substituted with    0, 1 or 2 substituents independently selected from the group    consisting of halo, —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a),    —NR_(a)R_(b), —NR_(b)C(O)R_(a)—N(R_(b))C(O)OR_(a),    —N(R_(a))C(═N)NR_(a)R_(b), —N(R_(a))C(O)NR_(a)R_(b),    —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(2a);-   R^(2a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(2a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R³ is alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, -alkylOR_(a),    -alkylSR_(a), -alkylSOR_(a), -alkylSO₂R_(a), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)OR_(a),    -alkylN(R_(a))C(═N)NR_(a)R_(b), -alkylN(R_(a))C(O)NR_(a)R_(b),    -alkylC(O)NR_(a)R_(b), -alkylC(O)OR_(a), cycloalkyl,    cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle,    heterocyclealkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;    wherein the cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl,    cycloalkyl moiety of the cycloalkylalkyl, cycloalkenyl moiety of the    cycloalkenylalkyl, heterocycle moiety of the heterocyclealkyl,    heteroaryl moiety of the heteroarylalkyl and the aryl moiety of the    arylalkyl are independently substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and    R^(3a);-   R^(3a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(3a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    oxo, alkyl, alkenyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), and -alkylC(O)N(alkyl)₂;-   R⁴ is H and R⁵ is OR¹⁶; or-   R⁵ is H and R⁴ is OR¹⁶; or-   R⁴ and R⁵ are —OR¹⁶;-   R⁶ is alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, -alkylOR_(a),    -alkylSR_(a), -alkylSOR_(a), -alkylSO₂R_(a), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)OR_(a),    -alkylN(R_(a))C(═N)NR_(a)R_(b), -alkylN(R_(a))C(O)NR_(a)R_(b),    -alkylC(O)NR_(a)R_(b), -alkylC(O)OR_(a), cycloalkyl,    cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle,    heterocyclealkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;    wherein the cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl,    cycloalkyl moiety of the cycloalkylalkyl, cycloalkenyl moiety of the    cycloalkenylalkyl, heterocycle moiety of the heterocyclealkyl,    heteroaryl moiety of the heteroarylalkyl and the aryl moiety of the    arylalkyl are independently substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and    R^(6a);-   R^(6a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(6a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    oxo, alkyl, alkenyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), and -alkylC(O)N(alkyl)₂;-   R⁷ is —N(R_(b))C(O)OR_(a), alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, heterocycle, aryl or heteroaryl; wherein the alkyl,    alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl and    heteroaryl are independently substituted with 0, 1 or 2 substituents    independently selected from the group consisting of halo, —OR_(a),    —OC(O)R_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —NR_(a)R_(b),    —N(R_(b))C(O)R_(a), —N(R_(b))C(O)OR_(a), —N(R_(a))C(═N)NR_(a)R_(b),    —N(R_(a))C(O)NR_(a)R_(b), —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(7a);-   R^(7a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(7a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R⁸ is —OR_(a), —NR_(a)R_(b), —N(R_(b))C(O)OR_(a), -alkylOR_(a),    -alkylOC(O)R_(a), or -alkylC(O)R_(a);-   R⁹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R⁹ is substituted with 0, 1,    2 or 3 substituents independently selected from the group consisting    of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro, oxo,    —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))SO₂R_(a),    —N(R_(b))SO₂NR_(a)R_(b), —N(R_(b))C(O)NR_(a)R_(b),    —N(R_(b))C(O)OR_(a), —C(O)R_(a), —C(O)NR_(a)R_(b), —C(O)OR_(a),    haloalkyl, nitroalkyl, cynaoalkyl, formylalkyl, -alkylOR_(a),    -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)OR_(a), -alkylN(R_(b))SO₂NR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkylC(O)R_(a),    -alkylC(O)NR_(a)R_(b) and R^(9a);-   R^(9a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(9a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹⁰ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R¹⁰ is substituted with 0,    1, 2 or 3 substituents independently selected from the group    consisting of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro,    oxo, —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))SO₂R_(a),    —N(R_(b))SO₂NR_(a)R_(b), —N(R_(b))C(O)NR_(a)R_(b),    —N(R_(b))C(O)OR_(a), —C(O)R_(a), —C(O)NR_(a)R_(b), —C(O)OR_(a),    haloalkyl, nitroalkyl, cynaoalkyl, formylalkyl, -alkylOR_(a),    -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)OR_(a), -alkylN(R_(b))SO₂NR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkylC(O)R_(a),    -alkylC(O)NR_(a)R_(b) and R^(10a);-   R^(10a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or    heteroaryl; wherein each R^(10a) is substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R¹¹ is substituted with 0,    1, 2 or 3 substituents independently selected from the group    consisting of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro,    oxo, —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))SO₂R_(a),    N(R_(b))SO₂NR_(a)R_(b), —N(R_(b))C(O)NR_(a)R_(b),    —N(R_(b))C(O)OR_(a), —C(O)R_(a), —C(O)NR_(a)R_(b), —C(O)OR_(a),    haloalkyl, nitroalkyl, cynaoalkyl, formylalkyl, -alkylOR_(a),    -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)OR_(a), -alkylN(R_(b))SO₂NR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkylC(O)R_(a),    -alkylC(O)NR_(a)R_(b) and R^(11a);-   R^(11a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or    heteroaryl; wherein each R^(11a) is substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R¹² is alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl or    cycloalkenylalkyl; wherein each R¹² is substituted with 0, 1 or 2    substituents independently selected from the group consisting of    hydroxy, alkoxy and halo;-   R¹³ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R¹³ is substituted with 0,    1, 2 or 3 substituents independently selected from the group    consisting of alkyl, alkenyl, alkynyl, cyano, halo, nitro, oxo,    —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))C(O)OR_(a),    —C(O)NR_(a)R_(b), —C(O)OR_(a), haloalkyl, nitroalkyl, cynaoalkyl,    -alkylOR_(a), -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkyl-C(O)NR_(a)R_(b) and    R^(13a);-   R^(13a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or    heteroaryl; wherein each R^(13a) is substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹⁴ is —OR_(a), -alkylOR_(a), aryl, heteroaryl or heterocycle;    wherein the aryl, heteroaryl and heterocycle are independently    substituted with 0, 1, 2, 3 or 4 substituents independently selected    from the group consisting of cyano, halo, nitro, oxo, alkyl,    alkenyl, alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂,    —SH, —S(alkyl), —SO₂(alkyl), —S(O)₂NR_(a)R_(b), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹⁶ is hydrogen or R¹⁵;

-   R₁₀₃ is C(R₁₀₅)₂, O or —N(R₁₀₅);-   R₁₀₄ is hydrogen, alkyl, haloalkyl, alkoxycarbonyl, aminocarbonyl,    alkylaminocarbonyl or dialkylaminocarbonyl,-   each M is independently selected from the group consisting of H,    —N(R₁₀₅)₂, alkyl, alkenyl, and R₁₀₆; wherein 1 to 4 —CH₂ radicals of    the alkyl or alkenyl, other than the —CH₂ radical that is bound to    Z, is optionally replaced by a heteroatom group selected from the    group consisting of O, S, S(O), SO₂ and N(R₁₀₅); and wherein any    hydrogen in said alkyl, alkenyl or R₁₀₆ is optionally replaced with    a substituent selected from the group consisting of oxo, —OR₁₀₅,    —R₁₀₅, —N(R₁₀₅)₂, —CN, —C(O)OR₁₀₅, —C(O)N(R₁₀₅)₂, —SO₂N(R₁₀₅),    —N(R₁₀₅)C(O)R₁₀₅, —C(O)R₁₀₅, —SR₁₀₅, —S(O)R₁₀₅, —SO₂R₁₀₅, —OCF₃,    —SR₁₀₆, —SOR₁₀₆, —SO₂R₁₀₆, —N(R₁₀₅)SO₂R₁₀₅, halo, —CF₃, NO₂ and    phenyl; provided that when M is —N(R₁₀₅)₂, Z₁ and Z₂ are —CH₂;-   Z₁ is CH₂, O, S, —N(R₁₀₅), or, when M is absent, H;-   Z₂ is CH₂, O, S or —N(R₁₀₅);-   Q is O or S;-   W is P or S; wherein when W is S, Z₁ and Z₂ are not S;-   M′ is H, alkyl, alkenyl or R₁₀₆; wherein 1 to 4 —CH₂ radicals of the    alkyl or alkenyl is optionally replaced by a heteroatom group    selected from O, S, S(O), SO₂, or N(R₁₀₅); and wherein any hydrogen    in said alkyl, alkenyl or R₁₀₆ is optionally replaced with a    substituent selected from the group consisting of oxo, —OR₁₀₅,    —R₁₀₅, —N(R₁₀₅)₂, —CN, —C(O)OR₁₀₅, —C(O)N(R₁₀₅)₂, —SO₂N(R₁₀₅),    —N(R₁₀₅)C(O)R₁₀₅, —C(O)R₁₀₅, —SR₁₀₅, —S(O)R₁₀₅, —SO₂R₁₀₅, —OCF₃,    —SR₁₀₆, —SOR₁₀₆, —SO₂R₁₀₆, —N(R₁₀₅)SO₂R₁₀₅, halo, —CF₃ and NO₂;-   R₁₀₆ is a monocyclic or bicyclic ring system selected from the group    consisting of aryl, cycloalkyl, cycloalkenyl heteroaryl and    heterocycle; wherein any of said heteroaryl and heterocycle ring    systems contains one or more heteroatoms selected from the group    consisting of O, N, S, SO, SO₂ and N(R₁₀₅); and wherein any of said    ring system is substituted with 0, 1, 2, 3, 4, 5 or 6 substituents    selected from the group consisting of hydroxy, alkyl, alkoxy, and    —OC(O)alkyl;-   each R₁₀₅ is independently selected from the group consisting of H    or alkyl; wherein said alkyl is optionally substituted with a ring    system selected from the group consisting of aryl, cycloalkyl,    cycloalkenyl, heteroaryl and heterocycle; wherein any of said    heteroaryl and heterocycle ring systems contains one or more    heteroatoms selected from the group consisting of O, N, S, SO, SO₂,    and N(R₁₀₅); and wherein any one of said ring systems is substituted    with 0, 1, 2, 3 or 4 substituents selected from the group consisting    of oxo, —OR₁₀₅, —R₁₀₅, —N(R₁₀₅)₂, —N(R₁₀₅)C(O)R₁₀₅, —CN, —C(O)OR₁₀₅,    —C(O)N(R₁₀₅)₂, halo and —CF₃; each R₁₀₇ and R₁₀₈ are independently    selected from the group consisting of hydrogen and alkyl;-   q is 0 or 1;-   m is 0 or 1;-   m′ is 0 or 1;-   m″ is 0 or 1;-   r is 0, 1, 2, 3 or 4;-   t is 0 or 1;-   R_(a) and R_(b) at each occurrence are independently selected from    the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    cycloalkyl, aryl, heteroaryl and heterocycle; wherein each R_(a) and    R_(b), at each occurrence, is independently substituted with 0, 1, 2    or 3 substituents independently selected from the group consisting    of cyano, nitro, halo, oxo, alkyl, alkenyl, alkynyl, hydroxy,    alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and R_(c);    alternatively, R_(a) and R_(b), together with the nitrogen atom to    which they are attached, form a ring selected from the group    consisting of heteroaryl and heterocycle; wherein each of the    heteroaryl and heterocycle is independently substituted with 0, 1, 2    or 3 substituents independently selected from the group consisting    of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo,    hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),    —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, formylalkyl,    nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH₂,    -alkylN(H)(alkyl), -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂,    -alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH,    -alkylC(O)Oalkyl, -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl),    -alkylC(O)N(alkyl)₂ and R_(c);-   R_(c) is aryl, heteroaryl or heterocycle; wherein each R_(c) is    independently substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of halo, nitro,    oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkyl-NH₂, -alkyl-N(H)(alkyl), -alkyl-N(alkyl)₂,    -alkyl-N(H)C(O)NH₂, -alkyl-N(H)C(O)N(H)(alkyl),    -alkyl-N(H)C(O)N(alkyl)₂, -alkyl-C(O)OH, -alkyl-C(O)Oalkyl,    -alkyl-C(O)NH₂, -alkyl-C(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂; and    n is 1 or 2.

For example, the present invention provides a compound of formula (XI)wherein L is —C(═O) or —C(═S), X is O; Y is O; and L, B, R^(A), R¹,R^(1a), R², R^(2a), R³, R^(3a), R⁴, R⁵, R⁶, R^(6a), R^(7a), R⁸, R⁹,R^(9a), R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R^(12a), R¹³, R^(13a), R¹⁴,R¹⁵, R^(15a), R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈,q, m, m′, m″, r, t, R_(a), R_(b), R_(c), and n are defined in formula(XI).

For example, the present invention provides a compound of formula (XI)wherein X is O, Y is O, R⁴ is H, R⁵ is OR¹⁶, R² is alkyl; and L, B,R^(A), R¹, R^(1a), R³, R^(3a), R⁶, R^(6a), R⁷, R^(7a), R⁸, R⁹, R^(9a),R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R^(12a), R¹³, R^(13a), R¹⁴, R¹⁵, R₁₆,R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″,r, t, R_(a), R_(b), R_(c), and n are defined in formula (XI).

For example, the present invention provides a compound of formula (XI)wherein X is O, Y is O, R is H, R⁵ is OR¹⁶, R² is alkyl, R³ isarylalkyl; and L, B, R^(A), R¹, R^(1a), R³, R^(3a), R⁶, R^(6a), R⁷,R^(7a), R⁸, R⁹, R^(9a), R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R^(12a), R¹³,R^(13a), R¹⁴, R^(14a), R¹⁵, R^(15a), R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂,Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(a), R_(b),R_(c), n and the substituents of the aryl moiety of arylalkyl of R³ aredefined in formula (XI).

For example, the present invention provides a compound of formula (XI)wherein X is O, Y is O, R⁴ is H, R⁵ is OR¹⁶, R² is alkyl and R³ isarylalkyl wherein the aryl moiety of the arylalkyl is substituted with 0or one R^(3a); and L, B, R^(A), R¹, R^(1a), R^(3a), R⁶, R^(6a), R⁷,R^(7a), R⁸, R⁹, R^(9a), R¹⁰ R^(10a), R¹¹, R^(11a), R¹², R^(12a), R¹³,R^(13a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂,Q, W, M′, R₁₀₆,R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c), and n are definedin formula (XI).

For example, the present invention provides a compound of formula (XI)wherein X is O, Y is O, R⁴ is H, R⁵ is OR¹⁶, R² is alkyl, R³ isarylalkyl wherein the aryl moiety of the arylalkyl is substituted with 0or one R^(3a) wherein R^(3a) is aryl or heteroaryl; and L, B, R^(A), R¹,R^(1a), R⁶, R^(6a), R⁷, R^(7a), R⁸, R⁹, R^(9a), R¹⁰, R^(10a), R¹¹,R^(11a), R¹², R^(12a), R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R¹⁰⁵, M,Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b),R_(c), n and the substituents of R^(3a) are defined in formula (XI).

For example, the present invention provides a compound of formula (XI)wherein X is O, Y is O, R⁴ is H, R⁵ is OR¹⁶, R² is alkyl, R¹ is alkyl,R³ is arylalkyl wherein the aryl moiety of the arylalkyl is substitutedwith 0 or one R^(3a) wherein R^(3a) is aryl or heteroaryl; and L, B,R^(A), R⁶, R^(6a), R⁷, R^(7a), R⁸, R^(8a), R⁹, R^(9a), R¹⁰, R^(10a),R¹¹, R^(11a), R¹², R^(12a), R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄,R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a),R_(b), R_(a), n and the substituents of R^(3a) are defined in formula(XI).

For example, the present invention provides a compound of formula (XI)wherein X is O, Y is O, R⁴ is H, R⁵ is OR¹⁶, R² is alkyl, R¹ is alkyl,R⁶is arylalkyl substituted with 0 or one R^(6a) wherein R^(6a) is arylor heteroaryl, and R³ is arylalkyl wherein the aryl moiety of thearylalkyl is substituted with 0 or one R^(3a) wherein R^(3a) is aryl orheteroaryl; and L, B, R^(A), R⁷, R^(7a), R⁸, R⁹, R^(9a), R¹⁰, R^(10a),R¹¹, R^(11a), R¹², R^(12a), R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄,R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a),R_(b), R_(c), n and the substituents of R^(3a) and R^(6a) are defined informula (XI).

For example, the present invention provides a compound of formula (XI)wherein X is O, Y is O, R⁴ is H, R⁵ is OR¹⁶, R² is alkyl, R¹ is alkyl,each R₁₀₄ is independently hydrogen or alkyl each R₁₀₅ is independentlyhydrogen or alkyl, each M is independently hydrogen or alkyl, Z₁ and Z₂are O, Q is O, W is P, R⁶ is arylalkyl substituted with 0 or one R^(6a)wherein R^(6a) is aryl or heteroaryl, and R³ is arylalkyl wherein thearyl moiety of the arylalkyl is substituted with 0 or one R^(3a) whereinR^(3a) is aryl or heteroaryl; and L, B, R^(A), R⁷, R^(7a), R⁸, R⁹,R^(9a), R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R^(12a), R¹³, R^(13a), R¹⁴,R¹⁵, R¹⁶, R₁₀₃, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b),R_(c), n and the substituents of R^(3a) and R^(6a) are defined informula (XI).

In a twelfth embodiment the present invention provides a compound offormula (XII)

or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, wherein:

-   A is

-   X is O, S or NH;-   Y is O, S or NH;-   B is H or —CH₂R⁹;-   L is —C(═O), —C(═S), —C(═NH) or —S(O)₂;-   R^(A) is —N(H)C(O)R⁸, —O(R_(a)), —OC(O)OR_(a), —NR_(a)R_(b),    —N(R_(b))S(O)₂R_(a), —N(R_(b))alkylN(R_(b))S(O)₂R_(a),    —N(R_(b))alkylN(R_(b))C(O)OR_(a),    —N(R_(b))alkylN(R_(b))C(O)NR_(a)R_(b), -alkylSR_(a), -alkylS(O)R_(a)    or -alkylS(O)₂R_(a);-   R¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,    heterocycle, aryl or heteroaryl; wherein each R¹ is substituted with    0, 1 or 2 substituents independently selected from the group    consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl,    hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),    —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂, and    R^(1a);-   R^(1a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(1a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R² is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,    heterocycle, aryl or heteroaryl; wherein each R² is substituted with    0, 1 or 2 substituents independently selected from the group    consisting of halo, —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a),    —NR_(a)R_(b), —NR_(b)C(O)R_(a—N(R) _(b))C(O)OR_(a),    —N(R_(a))C(═N)NR_(a)R_(b), —N(R_(a))C(O)NR_(a)R_(b),    —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(2a);-   R^(2a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(2a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R³ is alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, -alkylOR_(a),    -alkylSR_(a), -alkylSOR_(a), -alkylSO₂R_(a), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)OR_(a),    -alkylN(R_(a))C(═N)NR_(a)R_(b), -alkylN(R_(a))C(O)NR_(a)R_(b),    -alkylC(O)NR_(a)R_(b), -alkylC(O)OR_(a), cycloalkyl,    cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle,    heterocyclealkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;    wherein the cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl,    cycloalkyl moiety of the cycloalkylalkyl, cycloalkenyl moiety of the    cycloalkenylalkyl, heterocycle moiety of the heterocyclealkyl,    heteroaryl moiety of the heteroarylalkyl and the aryl moiety of the    arylalkyl are independently substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and    R^(3a);-   R^(3a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(3a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    oxo, alkyl, alkenyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), and -alkylC(O)N(alkyl)₂;-   R⁴ is H and R⁵ is OR¹⁶; or-   R⁵ is H and R⁴ is OR¹⁶; or-   R⁴ and R⁵ are —OR¹⁶;-   R⁶ is alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, -alkylOR_(a),    -alkylSR_(a), -alkylSOR_(a), -alkylSO₂R_(a), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)OR_(a),    -alkylN(R_(a))C(═N)NR_(a)R_(b), -alkylN(R_(a))C(O)NR_(a)R_(b),    -alkylC(O)NR_(a)R_(b), -alkylC(O)OR_(a), cycloalkyl,    cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle,    heterocyclealkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;    wherein the cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl,    cycloalkyl moiety of the cycloalkylalkyl, cycloalkenyl moiety of the    cycloalkenylalkyl, heterocycle moiety of the heterocyclealkyl,    heteroaryl moiety of the heteroarylalkyl and the aryl moiety of the    arylalkyl are independently substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and    R^(6a);-   R^(6a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(6a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    oxo, alkyl, alkenyl, hydroxy, alkoxy, —NH₂, N(H)(alkyl), —N(alkyl)₂,    —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl,    —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH,    —C(O)Oalkyl, —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), and -alkylC(O)N(alkyl)₂;-   R⁷ is —N(R_(b))C(O)OR_(a), alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, heterocycle, aryl or heteroaryl; wherein the alkyl,    alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl and    heteroaryl are independently substituted with 0, 1 or 2 substituents    independently selected from the group consisting of halo, —OR_(a),    —OC(O)R_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —NR_(a)R_(b),    —N(R_(b))C(O)R_(a), —N(R_(b))C(O)OR_(a), —N(R_(a))C(═N)NR_(a)R_(b),    —N(R_(a))C(O)NR_(a)R_(b), —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(7a);-   R^(7a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(7a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R⁸ is —OR_(a), —NR_(a)R_(b), —N(R_(b))C(O)OR_(a), -alkylOR_(a),    -alkylOC(O)R_(a), or —O-alkylC(O)R_(a);-   R⁹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R⁹ is substituted with 0, 1,    2 or 3 substituents independently selected from the group consisting    of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro, oxo,    —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a),    —NR_(a)R_(b), —N(R)C(O)R_(a), —N(R_(b))SO₂R_(a),    —N(R_(b))SO₂NR_(a)R_(b), —N(R_(b))C(O)NR_(a)R_(b),    —N(R_(b))C(O)OR_(a), —C(O)R_(a), —C(O)NR_(a)R_(b), —C(O)OR_(a),    haloalkyl, nitroalkyl, cynaoalkyl, formylalkyl, -alkylOR_(a),    -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)OR_(a), -alkylN(R_(b))SO₂NR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkylC(O)R_(a),    -alkylC(O)NR_(a)R_(b) and R^(9a);-   R^(9a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(9a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹⁰ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R¹⁰ is substituted with 0,    1, 2 or 3 substituents independently selected from the group    consisting of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro,    oxo, —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))SO₂R_(a),    —N(R_(b))SO₂NR_(a)R_(b), —N(R_(b))C(O)NR_(a)R_(b),    —N(R_(b))C(O)OR_(a), —C(O)R_(a), —C(O)NR_(a)R_(b), —C(O)OR_(a),    haloalkyl, nitroalkyl, cynaoalkyl, formylalkyl, -alkylOR_(a),    -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)OR_(a), -alkylN(R_(b))SO₂NR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkylC(O)R_(a),    -alkylC(O)NR_(a)R_(b) and R^(10a);-   R^(10a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or    heteroaryl; wherein each R^(10a) is substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R¹¹ is substituted with 0,    1, 2 or 3 substituents independently selected from the group    consisting of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro,    oxo, —OR_(a), —SR_(a), —SOR_(a), SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))SO₂R_(a),    —N(R_(b))SO₂NR_(a)R_(b), —N(R_(b))C(O)NR_(a)R_(b),    —N(R_(b))C(O)OR_(a), —C(O)R_(a), —C(O)NR_(a)R_(b), —C(O)OR_(a),    haloalkyl, nitroalkyl, cynaoalkyl, formylalkyl, -alkylOR_(a),    -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)OR_(a), -alkylN(R_(b))SO₂NR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkylC(O)R_(a),    -alkylC(O)NR_(a)R_(b) and R^(11a);-   R^(11a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or    heteroaryl; wherein each R^(11a) is substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R¹² is alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl or    cycloalkenylalkyl; wherein each R¹² is substituted with 0, 1 or 2    substituents independently selected from the group consisting of    hydroxy, alkoxy and halo;-   R¹³ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R¹³ is substituted with 0,    1, 2 or 3 substituents independently selected from the group    consisting of alkyl, alkenyl, alkynyl, cyano, halo, nitro, oxo,    —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))C(O)OR_(a),    —C(O)NR_(a)R_(b), —C(O)OR_(a), haloalkyl, nitroalkyl, cynaoalkyl,    -alkylOR_(a), -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkyl-C(O)NR_(a)R_(b) and    R^(13a);-   R^(13a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or    heteroaryl; wherein each R^(13a) is substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹⁴ is —OR_(a), -alkylOR_(a), aryl, heteroaryl or heterocycle;    wherein the aryl, heteroaryl and heterocycle are independently    substituted with 0, 1, 2, 3 or 4 substituents independently selected    from the group consisting of cyano, halo, nitro, oxo, alkyl,    alkenyl, alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂,    —SH, —S(alkyl), —SO₂(alkyl), —S(O)₂NR_(a)R^(b), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹⁶ is hydrogen or R¹⁵;

-   R₁₀₃ is C(R₁₀₅)₂, O or —N(R₁₀₅);-   R₁₀₄ is hydrogen, alkyl, haloalkyl, alkoxycarbonyl, aminocarbonyl,    alkylaminocarbonyl or dialkylaminocarbonyl,-   each M is independently selected from the group consisting of H,    —N(R₁₀₅)₂, alkyl, alkenyl, and R₁₀₆; wherein 1 to 4 —CH₂ radicals of    the alkyl or alkenyl, other than the —CH₂ radical that is bound to    Z, is optionally replaced by a heteroatom group selected from the    group consisting of O, S, S(O), SO₂ and N(R₁₀₅); and wherein any    hydrogen in said alkyl, alkenyl or R₁₀₆ is optionally replaced with    a substituent selected from the group consisting of oxo, —OR₁₀₅,    —R₁₀₅, —N(R₁₀₅)₂, —CN, —C(O)OR₁₀₅, —C(O)N(R₁₀₅)₂, —SO₂N(R₁₀₅),    —N(R₁₀₅)C(O)R₁₀₅, —C(O)R₁₀₅, —SR₁₀₅, —S(O)R₁₀₅, —SO₂R₁₀₅, —OCF₃,    —SR₁₀₆, —SOR₁₀₆, —SO₂R₁₀₆, —N(R₁₀₅)SO₂R₁₀₅, halo —CF₃, NO₂ and    phenyl; provided that when M is —N(R₁₀₅)₂, Z₁ and Z₂ are —CH₂;-   Z₁ is CH₂, O, S, N(R₁₀₅), or, when M is absent, H;-   Z₂ is CH₂, O, S or —N(R₁₀₅);-   Q is O or S;-   W is P or S; wherein when W is S, Z₁ and Z₂ are not S;-   M′ is H, alkyl, alkenyl or R₁₀₆; wherein 1 to 4 —CH₂ radicals of the    alkyl or alkenyl is optionally replaced by a heteroatom group    selected from O, S, S(O), SO, or N(R₁₀₅); and wherein any hydrogen    in said alkyl, alkenyl or R₁₀₆ is optionally replaced with a    substituent selected from the group consisting of oxo, —OR₁₀₅,    —R₁₀₅, —N(R₁₀₅)₂, —CN, —C(O)OR₁₀₅, —C(O)N(R₁₀₅)₂, —SO₂N(R₁₀₅),    —N(R₁₀₅)C(O)R₁₀₅, —C(O)R₁₀₅, —SR₁₀₅, —S(O)R₁₀₅, —SO₂R₁₀₅, —OCF₃,    —SR₁₀₆, —SOR₁₀₆, —SO₂R₁₀₆, —N(R₁₀₅)SO₂R₁₀₅, halo, —CF₃ and NO₂;-   R₁₀₆ is a monocyclic or bicyclic ring system selected from the group    consisting of aryl, cycloalkyl, cycloalkenyl heteroaryl and    heterocycle; wherein any of said heteroaryl and heterocycle ring    systems contains one or more heteroatoms selected from the group    consisting of O, N, S, SO, SO₂ and N(R₁₀₅); and wherein any of said    ring system is substituted with 0, 1, 2, 3, 4, 5 or 6 substituents    selected from the group consisting of hydroxy, alkyl, alkoxy, and    —OC(O)alkyl;-   each R₁₀₅ is independently selected from the group consisting of H    or alkyl; wherein said alkyl is optionally substituted with a ring    system selected from the group consisting of aryl, cycloalkyl,    cycloalkenyl, heteroaryl and heterocycle; wherein any of said    heteroaryl and heterocycle ring systems contains one or more    heteroatoms selected from the group consisting of O, N, S, SO, SO₂,    and N(R₁₀₅); and wherein any one of said ring systems is substituted    with 0, 1, 2, 3 or 4 substituents selected from the group consisting    of oxo, —OR₁₀₅, —R₁₀₅, —N(R₁₀₅)₂, —N(R₁₀₅)C(O)R₁₀₅, —CN,    —C(O)N(R₁₀₅)₂, halo and —CF₃;-   each R₁₀₇ and R₁₀₈ are independently selected from the group    consisting of hydrogen and alkyl;-   q is 0 or 1;-   m is 0 or 1;-   m′ is 0 or 1;-   m″ is 0 or 1;-   r is 0, 1, 2, 3 or 4;-   t is 0 or 1;-   R^(a) and R^(b) at each occurrence are independently selected from    the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    cycloalkyl, aryl, heteroaryl and heterocycle; wherein each R_(a) and    R_(b), at each occurrence, is independently substituted with 0, 1, 2    or 3 substituents independently selected from the group consisting    of cyano, nitro, halo, oxo, alkyl, alkenyl, alkynyl, hydroxy,    alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and R_(c);-   alternatively, R_(a) and R_(b), together with the nitrogen atom to    which they are attached, form a ring selected from the group    consisting of heteroaryl and heterocycle; wherein each of the    heteroaryl and heterocycle is independently substituted with 0, 1, 2    or 3 substituents independently selected from the group consisting    of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo,    hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),    —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, formylalkyl,    nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH₂,    -alkylN(H)(alkyl), -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂,    -alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH,    -alkylC(O)Oalkyl, -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl),    -alkylC(O)N(alkyl)₂ and R_(c);-   R_(c) is aryl, heteroaryl or heterocycle; wherein each R_(a) is    independently substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of halo, nitro,    oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkyl-NH₂, -alkyl-N(H)(alkyl), -alkyl-N(alkyl)₂,    -alkyl-N(H)C(O)NH₂, -alkyl-N(H)C(O)N(H)(alkyl),    -alkyl-N(H)C(O)N(alkyl)₂, -alkyl-C(O)OH, -alkyl-C(O)Oalkyl,    -alkyl-C(O)NH₂, -alkyl-C(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂; and    n is 1 or 2.

For example, the present invention provides a compound of formula (XII)wherein L is —C(═O) or —C(═S), X is O; Y is O; and L, B, R^(A), R¹,R^(1a), R², R^(2a), R³, R^(3a), R⁴, R⁵, R⁶, R^(6a), R⁷, R^(7a), R⁸, R⁹,R^(9a), R¹⁰, R_(10a), R¹¹, R^(11a), R¹², R^(12a), R¹³, R^(13a), R¹⁴,R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z_(a), Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q,m, m′, m″, r, t, R_(a), R_(b), R_(a), and n are defined in formula(XII).

For example, the present invention provides a compound of formula (XII)wherein X is O, Y is O, R⁴ is H, R⁵ is OR¹⁶, R² is alkyl; and L, B,R^(A), R¹, R^(1a), R³, R^(3a), R⁶, R^(6a), R⁷, R^(7a), R⁸, R⁹, R^(9a),R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R^(12a), R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶,R₁₀₃, R₁₀₄, R_(105, M, Z) ₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′,m″, r, t, R_(a), R_(b), R_(a), and n are defined in formula (XII).

For example, the present invention provides a compound of formula (XII)wherein X is O, Y is O, R⁴ is H, R⁵ is OR¹⁶, R² is alkyl, R³ isarylalkyl; and L, B, R^(A), R¹, R^(1a), R^(3a), R⁶, R^(6a), R⁷, R⁸, R⁹,R^(9a), R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R^(12a), R¹³, R^(13a), R¹⁴,R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z_(a), Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q,m, m′, m″, r, t, R_(a), R_(b), R_(c), n and the substituents of the arylmoiety of arylalkyl of R³ are defined in formula (XII).

For example, the present invention provides a compound of formula (XII)wherein X is O, Y is O, R⁴ is H, R⁵ is OR¹⁶, R² is alkyl and R³ isarylalkyl wherein the aryl moiety of the arylalkyl is substituted with 0or one R^(3a); and L, B, R^(A), R¹, R^(1a), R³, R^(3a), R⁶, R^(6a), R⁷,R^(7a), R⁸, R⁹, R_(9a), R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R^(12a), R¹³,R^(13a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R_(104,) R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆,R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c), and n are definedin formula (XII).

For example, the present invention provides a compound of formula (XII)wherein X is O, Y is O, R⁴ is H, R⁵ is OR¹⁶, R² is alkyl, R³ isarylalkyl wherein the aryl moiety of the arylalkyl is substituted with 0or one R^(3a) wherein R^(3a) is aryl or heteroaryl; and L, B, R^(A), R¹,R^(1a), R⁶, R^(6a), R⁷, R^(7a), R⁸, R⁹, R^(9a), R¹⁰, R^(10a), R¹¹,R^(11a), R¹², R^(12a), R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M,Z_(a), Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b),R_(c), n and the substituents of R^(3a) are defined in formula (XII).

For example, the present invention provides a compound of formula (XII)wherein X is O, Y is O, R⁴ is H, R⁵ is OR¹⁶, R² is alkyl, R¹ is alkyl,R³ is arylalkyl wherein the aryl moiety of the arylalkyl is substitutedwith 0 or one R^(3a) wherein R^(3a) is aryl or heteroaryl; and L, B,R^(A), R⁶, R^(6a), R⁷, R⁸, R⁹, R^(9a), R¹⁰, R^(10a), R¹¹, R^(11a), R¹²,R^(12a), R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R¹⁰⁵, M, Z₁, Z₂, Q, W, M′,R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c), n and thesubstituents of R^(3a) are defined in formula (XII).

For example, the present invention provides a compound of formula (XII)wherein X is O, Y is O, R⁴ is H, R⁵ is OR¹⁶, R² is alkyl, R¹ is alkyl,R⁶ is arylalkyl substituted with 0 or one R^(6a) wherein R^(6a) is arylor heteroaryl, and R³ is arylalkyl wherein the aryl moiety of thearylalkyl is substituted with 0 or one R^(3a) wherein R^(3a) is aryl orheteroaryl; and L, B, R^(A), R⁷, R^(7a), R⁸, R⁹, R^(9a), R¹⁰, R^(10a),R¹¹, R_(11a), R¹², R^(12a), R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄,R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a),R_(b), R_(c), n and the substituents of R^(3a) and R^(6a) are defined informula (XII).

For example, the present invention provides a compound of formula (XII)wherein X is O, Y is O, R⁴ is H, R⁵ is OR¹⁶, R² is alkyl, R¹ is alkyl,each R₁₀₄ is independently hydrogen or alkyl, each R₁₀₅ is independentlyhydrogen or alkyl, each M is independently hydrogen or alkyl, Z₁ and Z₂are O, Q is O, W is P, It is arylalkyl substituted with 0 or one R^(6a)wherein R^(6a) is aryl or heteroaryl, and R³ is arylalkyl wherein thearyl moiety of the arylalkyl is substituted with 0 or one R^(3a) whereinR^(3a) is aryl or heteroaryl; and L, B, R^(A), R⁷, R^(7a), R⁸, R⁹,R^(9a), R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R^(12a), R¹³, R^(13a), R¹⁴,R¹⁵, R¹⁶, R₁₀₃, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b),R_(c), n and the substituents of R^(3a) and R^(6a) are defined informula (XII).

In a thirteenth embodiment the present invention provides a compound offormula (XIII)

or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, wherein:

-   A is

-   X is O, S or NH;-   Y is O, S or NH;-   B is H or —CH₂R⁹;-   L is —C(═O), —C(═S), C(═NH) or —S(O)₂;-   R^(A) is —N(H)C(O)R⁸, —O(R_(a)), —OC(O)OR_(a), —NR_(a)R_(b),    —N(R_(b))S(O)₂R_(a), —N(R_(b))alkylN(R_(b))S(O)₂R_(a),    —N(R_(b))alkylN(R_(b))C(O)OR_(a),    —N(R_(b))alkylN(R_(b))C(O)NR_(a)R_(b), -alkylSR_(a), -alkylS(O)R_(a)    or -alkylS(O)₂R_(a);-   R¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,    heterocycle, aryl or heteroaryl; wherein each R¹ is substituted with    0, 1 or 2 substituents independently selected from the group    consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl,    hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),    —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂, and    R^(1a);-   R^(1a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(1a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R² is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,    heterocycle, aryl or heteroaryl; wherein each R² is substituted with    0, 1 or 2 substituents independently selected from the group    consisting of halo, —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a),    —NR_(a)R_(b), —NR_(b)C(O)R_(a)—N(R_(b))C(O)OR_(a),    —N(R_(a))C(═N)NR_(a)R_(b), —N(R_(a))C(O)NR_(a)R_(b),    —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(2a);-   R^(2a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(2a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R³ is alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, -alkylOR_(a),    -alkylSR_(a), -alkylSOR_(a), -alkylSO₂R_(a), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)OR_(a),    -alkylN(R_(a))C(═N)NR_(a)R_(b), -alkylN(R_(a))C(O)NR_(a)R_(b),    -alkylC(O)NR_(a)R_(b), -alkylC(O)OR_(a), cycloalkyl,    cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle,    heterocyclealkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;    wherein the cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl,    cycloalkyl moiety of the cycloalkylalkyl, cycloalkenyl moiety of the    cycloalkenylalkyl, heterocycle moiety of the heterocyclealkyl,    heteroaryl moiety of the heteroarylalkyl and the aryl moiety of the    arylalkyl are independently substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and    R^(3a);-   R^(3a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(3a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    oxo, alkyl, alkenyl, hydroxy, alkoxy, —NH₂, N(H)(alkyl), —N(alkyl)₂,    —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl,    —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH,    —C(O)Oalkyl, —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), and -alkylC(O)N(alkyl)₂;-   R⁴ is H and R⁵ is OR¹⁶; or-   R⁵ is H and R⁴ is OR¹⁶; or-   R⁴ and R⁵ are —OR¹⁶;-   R is alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, -alkylOR_(a),    -alkylSR_(a), -alkylSOR_(a), -alkylSO₂R_(a), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)OR_(a),    -alkylN(R_(a))C(═N)NR_(a)R_(b), -alkylN(R_(a))C(O)NR_(a)R_(b),    -alkylC(O)NR_(a)R_(b), -alkylC(O)OR_(a), cycloalkyl,    cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle,    heterocyclealkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;    wherein the cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl,    cycloalkyl moiety of the cycloalkylalkyl, cycloalkenyl moiety of the    cycloalkenylalkyl, heterocycle moiety of the heterocyclealkyl,    heteroaryl moiety of the heteroarylalkyl and the aryl moiety of the    arylalkyl are independently substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and    R^(6a);-   R^(6a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(6a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    oxo, alkyl, alkenyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), and -alkylC(O)N(alkyl)₂;-   R⁷ is —N(R_(b))C(O)OR_(a), alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, heterocycle, aryl or heteroaryl; wherein the alkyl,    alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl and    heteroaryl are independently substituted with 0, 1 or 2 substituents    independently selected from the group consisting of halo, —OR_(a),    —OC(O)R_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —NR_(a)R_(b),    —N(R_(b))C(O)R_(a), —N(R_(b))C(O)OR_(a), —N(R_(a))C(═N)NR_(a)R_(b),    —N(R_(a))C(O)NR_(a)R_(b), —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(7a);-   R^(7a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(7a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R⁸ is —OR_(a), —NR_(a)R_(b) , —N(R_(b))C(O)OR_(a), -alkylOR_(a),    -alkylOC(O)R_(a), or —O-alkylC(O)R_(a);-   R⁹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R⁹ is substituted with 0, 1,    2 or 3 substituents independently selected from the group consisting    of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro, oxo,    —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))SO₂R_(a),    —N(R_(b))SO₂NR_(a)R_(b), —N(R_(b))C(O)NR_(a)R_(b),    —N(R_(b))C(O)OR_(a), —C(O)R_(a), —C(O)NR_(a)R_(b), —C(O)OR_(a),    haloalkyl, nitroalkyl, cynaoalkyl, formylalkyl, -alkylOR_(a),    -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)OR_(a), -alkylN(R_(b))SO₂NR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkylC(O)R_(a),    -alkylC(O)NR_(a) and R^(9a);-   R^(9a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(9a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹⁰ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R¹⁰ is substituted with 0,    1, 2 or 3 substituents independently selected from the group    consisting of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro,    oxo, —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), —SO₂R_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))SO₂R_(a),    —N(R_(b))SO₂NR_(a)R_(b), —N(R_(b))C(O)NR_(a)R_(b),    —N(R_(b))C(O)OR_(a), —C(O)R_(a), —C(O)NR_(a)R_(b), —C(O)OR_(a),    haloalkyl, nitroalkyl, cynaoalkyl, formylalkyl, -alkylOR_(a),    -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)OR_(a), -alkylN(R_(b))SO₂NR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkylC(O)R_(a),    -alkylC(O)NR_(a)R_(b) and R^(10a);-   R^(10a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or    heteroaryl; wherein each R^(10a) is substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R¹¹ is substituted with 0,    1, 2 or 3 substituents independently selected from the group    consisting of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro,    oxo, —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))SO₂R_(a),    —N(R_(b))SO₂NR_(a)R_(b), —N(R_(b))C(O)NR_(a)R_(b),    —N(R_(b))C(O)OR_(a), —C(O)R_(a), —C(O)NR_(a)R_(b), —C(O)OR_(a),    haloalkyl, nitroalkyl, cynaoalkyl, formylalkyl, -alkylOR_(a),    -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)OR_(a), -alkylN(R_(b))SO₂NR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkylC(O)R_(a),    -alkylC(O)NR_(a)R_(b) and R^(11a);-   R^(11a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or    heteroaryl; wherein each R^(11a) is substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R¹² is alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl or    cycloalkenylalkyl; wherein each R¹² is substituted with 0, 1 or 2    substituents independently selected from the group consisting of    hydroxy, alkoxy and halo;-   R¹³ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R¹³ is substituted with 0,    1, 2 or 3 substituents independently selected from the group    consisting of alkyl, alkenyl, alkynyl, cyano, halo, nitro, oxo,    —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))C(O)OR_(a),    —C(O)NR_(a)R_(b), —C(O)OR_(a), haloalkyl, nitroalkyl, cynaoalkyl,    -alkylOR_(a), -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkyl-C(O)NR_(a)R_(b) and    R^(13a);-   R^(13a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or    heteroaryl; wherein each R^(13a) is substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹⁴ is —OR_(a), -alkylOR_(a), aryl, heteroaryl or heterocycle;    wherein the aryl, heteroaryl and heterocycle are independently    substituted with 0, 1, 2, 3 or 4 substituents independently selected    from the group consisting of cyano, halo, nitro, oxo, alkyl,    alkenyl, alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂,    —SH, —S(alkyl), —SO₂(alkyl), —S(O)₂NR_(a)R_(b), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹⁶ is hydrogen or R¹⁵;-   R¹⁵ is

-   R₁₀₃ is C(R₁₀₅)₂, O or —N(R₁₀₅);-   R₁₀₄ is hydrogen, alkyl, haloalkyl, alkoxycarbonyl, aminocarbonyl,    alkylaminocarbonyl or dialkylaminocarbonyl,-   each M is independently selected from the group consisting of H,    —N(R₁₀₅)₂, alkyl, alkenyl, and R₁₀₆; wherein 1 to 4 —CH₂ radicals of    the alkyl or alkenyl, other than the —CH₂ radical that is bound to    Z, is optionally replaced by a heteroatom group selected from the    group consisting of O, S, S(O), SO₂ and N(R₁₀₅); and wherein any    hydrogen in said alkyl, alkenyl or R₁₀₆ is optionally replaced with    a substituent selected from the group consisting of oxo, —OR₁₀₅,    —R₁₀₅, —N(R₁₀₅)₂, —CN, —C(O)OR₁₀₅, —C(O)N(R₁₀₅)₂, —SO₂N(R₁₀₅),    —N(R₁₀₅)C(O)R₁₀₅, —C(O)R₁₀₅, —SR₁₀₅, —S(O)R₁₀₅, —SO₂R₁₀₅, —OCF₃,    —SR₁₀₆, —SOR₁₀₆, —SO₂R₁₀₆, —N(R₁₀₅)SO₂R₁₀₅, halo, —CF₃, NO(₂ and    phenyl; provided that when M is —N(R₁₀₅)₂, Z_(a) and Z₂ are —CH₂;-   Z₁ is CH₂, O, S, —N(R₁₀₅), or, when M is absent, H;-   Z₂ is CH₂, O, S or —N(R₁₀₅);-   Q is O or S;-   W is P or S; wherein when W is S, Z_(a) and Z₂ are not S;-   M′ is H, alkyl, alkenyl or R₁₀₆; wherein 1 to 4 —CH₂ radicals of the    alkyl or alkenyl is optionally replaced by a heteroatom group    selected from O, S, S(O), SO₂, or N(R₁₀₅); and wherein any hydrogen    in said alkyl, alkenyl or R₁₀₆ is optionally replaced with a    substituent selected from the group consisting of oxo, —OR₁₀₅,    —R₁₀₅, —N(R₁₀₅)₂, —CN, —C(O)OR₁₀₅, —C(O)N(R₁₀₅)₂, —SO₂N(R₁₀₅),    —N(R₁₀₅)C(O)R₁₀₅, —C(O)R₁₀₅, —SR₁₀₅, —S(O)R₁₀₅, —SO₂R₁₀₅, —OCF₃,    —SR₁₀₆, —SOR₁₀₆, —SO₂R₁₀₆, —N(R₁₀₅)SO₂R₁₀₅, halo, —CF₃ and NO₂;-   R₁₀₆ is a monocyclic or bicyclic ring system selected from the group    consisting of aryl, cycloalkyl, cycloalkenyl heteroaryl and    heterocycle; wherein any of said heteroaryl and heterocycle ring    systems contains one or more heteroatoms selected from the group    consisting of O, N, S, SO, SO₂ and N(R₁₀₅); and wherein any of said    ring system is substituted with 0, 1, 2, 3, 4, 5 or 6 substituents    selected from the group consisting of hydroxy, alkyl, alkoxy, and    —OC(O)alkyl;-   each R₁₀₅ is independently selected from the group consisting of H    or alkyl; wherein said alkyl is optionally substituted with a ring    system selected from the group consisting of aryl, cycloalkyl,    cycloalkenyl, heteroaryl and heterocycle; wherein any of said    heteroaryl and heterocycle ring systems contains one or more    heteroatoms selected from the group consisting of O, N, S, SO, SO₂,    and N(R₁₀₅); and wherein any one of said ring systems is substituted    with 0, 1, 2, 3 or 4 substituents selected from the group consisting    of oxo, —OR₁₀₅, —R₁₀₅, —N(R₁₀₅)₂, —N(R₁₀₅)C(O)R₁₀₅, —CN, —C(O)OR₁₀₅,    —C(O)N(R₁₀₅)₂, halo and —CF₃;-   each R₁₀₇ and R₁₀₈ are independently selected from the group    consisting of hydrogen and alkyl;-   q is 0 or 1;-   m is 0 or 1;-   m′ is 0 or 1;-   m″ is 0 or 1;-   r is 0, 1, 2, 3 or 4;-   t is 0 or 1;-   R_(a) and R_(b) at each occurrence are independently selected from    the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    cycloalkyl, aryl, heteroaryl and heterocycle; wherein each R_(a) and    R_(b), at each occurrence, is independently substituted with 0, 1, 2    or 3 substituents independently selected from the group consisting    of cyano, nitro, halo, oxo, alkyl, alkenyl, alkynyl, hydroxy,    alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and R_(c);-   alternatively, R_(a) and R_(b), together with the nitrogen atom to    which they are attached, form a ring selected from the group    consisting of heteroaryl and heterocycle; wherein each of the    heteroaryl and heterocycle is independently substituted with 0, 1, 2    or 3 substituents independently selected from the group consisting    of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo,    hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),    —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, formylalkyl,    nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH₂,    -alkylN(H)(alkyl), -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂,    -alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH,    -alkylC(O)Oalkyl, -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl),    -alkylC(O)N(alkyl)₂ and R_(c);-   R_(c) is aryl, heteroaryl or heterocycle; wherein each R_(c) is    independently substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of halo, nitro,    oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkyl-NH₂, -alkyl-N(H)(alkyl), -alkyl-N(alkyl)₂,    -alkyl-N(H)C(O)NH₂, -alkyl-N(H)C(O)N(H)(alkyl),    -alkyl-N(H)C(O)N(alkyl)₂, -alkyl-C(O)OH, -alkyl-C(O)Oalkyl,    -alkyl-C(O)NH₂, -alkyl-C(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂; and    n is 1 or 2.

For example, the present invention provides a compound of formula (XIII)wherein L is —C(═O) or —C(═S), X is O; Y is O; and L, B, R^(A), R¹,R^(1a), R², R^(2a), R³, R^(3a), R⁴, R⁵, R⁶, R^(6a), R⁷, R^(7a), R⁸, R⁹,R^(9a), R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R^(12a), R¹³, R^(13a), R¹⁴,R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m,m′, m″, r, t, R_(a), R_(b), R_(a), and n are defined in formula (XIII).

For example, the present invention provides a compound of formula (XIII)wherein X is O, Y is O, R⁴ is H, R⁵ is OR¹⁶, R²is alkyl; and L, B,R^(A), R¹, R^(1a), R³, R^(3a), R⁶, R^(6a), R⁷, R^(7a), R⁸, R⁹, R^(9a),R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R^(12a), R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶,R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″,r, t, R_(a), R_(b), R_(c), and n are defined in formula (XIII).

For example, the present invention provides a compound of formula (XIII)wherein X is O, Y is O, R⁴ is H, R⁵ is OR¹⁶ R² is alkyl, R³ isarylalkyl; and L, B, R^(A), R¹, R^(1a), R^(3a), R⁶, R^(6a), R⁷, R^(7a),R⁸, R⁹, R^(9a), R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R^(12a), R¹³, R^(13a),R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈,q, m, m′, m″, r, t, R_(a), R_(b), R_(c), n and the substituents of thearyl moiety of arylalkyl of R³ are defined in formula (XIII).

For example, the present invention provides a compound of formula (XIII)wherein X is O, Y is O, R⁴ is H, R⁵ is OR¹⁶, R² is alkyl and R³ isarylalkyl wherein the aryl moiety of the arylalkyl is substituted with 0or one R^(3a); and L, B, R^(A), R¹, R^(1a), R^(3a), R⁶, R^(6a), R⁷,R^(7a), R⁸, R⁹, R^(9a), R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R^(12a), R¹³,R^(13a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆,R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b), R_(c), and n are definedin formula (XIII).

For example, the present invention provides a compound of formula (XIII)wherein X is O, Y is O, R⁴ is H, R⁵ is OR¹⁶, R² is alkyl, R³ isarylalkyl wherein the aryl moiety of the arylalkyl is substituted with 0or one R^(3a) wherein R^(3a) is aryl or heteroaryl; and L, B, R^(A), R¹,R^(1a), R⁶, R^(6a), R⁷, R^(7a), R⁸, R⁹, R^(9a), R¹⁰, R^(10a), R¹¹,R^(11a), R¹², R^(12a), R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M,Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b),R_(c), n and the substituents of R^(3a) are defined in formula (XIII).

For example, the present invention provides a compound of formula (XIII)wherein X is O, Y is O, R⁴ is H, R⁵ is OR¹⁶, R² is alkyl, R¹ is alkyl,R³ is arylalkyl wherein the aryl moiety of the arylalkyl is substitutedwith 0 or one R^(3a) wherein R^(3a) is aryl or heteroaryl; and L, B,R^(A), R⁶, R^(6a), R⁷, R^(7a), R⁸, R⁹, R^(9a), R¹⁰, R^(10a), R¹¹,R^(11a), R¹², R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄, R₁₀₅, M, Z₁, Z₂,Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈ q, m, m′, m″, r, t, R_(a), R_(b), R_(c), nand the substituents of R^(3a) are defined in formula (XIII).

For example, the present invention provides a compound of formula (XIII)wherein X is O, Y is O, R⁴ is H, R⁵ is OR¹⁶, R² is alkyl, R¹ is alkyl,R⁶ is arylalkyl substituted with 0 or one R^(6a) wherein R^(6a) is arylor heteroaryl, and R³ is arylalkyl wherein the aryl moiety of thearylalkyl is substituted with 0 or one R^(3a) wherein R^(3a) is aryl orheteroaryl; and L, B, R^(A), R⁷, R^(7a), R⁸, R⁹, R^(9a), R¹⁰, R^(10a),R¹¹, R^(11a), R¹², R^(12a), R¹³, R^(13a), R¹⁴, R¹⁵, R¹⁶, R₁₀₃, R₁₀₄,R₁₀₅, M, Z₁, Z₂, Q, W, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a),R_(b), R_(c), n and the substituents of R^(3a) and R^(6a) are defined informula (XIII).

For example, the present invention provides a compound of formula (XIII)wherein X is O, Y is O, R⁴ is H, R⁵ is OR¹⁶, R² is alkyl, R¹ is alkyl,each R₁₀₄ is independently hydrogen or alkyl, each R₁₀₅ is independentlyhydrogen or alkyl, each M is independently hydrogen or alkyl, Z₁ and Z₂are O, Q is O, W is P, R⁶ is arylalkyl substituted with 0 or one R^(6a)wherein R^(6a) is aryl or heteroaryl, and R³ is arylalkyl wherein thearyl moiety of the arylalkyl is substituted with 0 or one R^(3a) whereinR^(3a) is aryl or heteroaryl; and L, B, R^(A), R⁷, R^(7a), R⁸, R⁹,R^(9a), R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R^(12a), R¹³, R^(13a), R¹⁴,R¹⁵, R¹⁶, R₁₀₃, M′, R₁₀₆, R₁₀₇, R₁₀₈, q, m, m′, m″, r, t, R_(a), R_(b),R_(c), n and the substituents of R^(3a) and R^(6a) are defined informula (XIII).

In a fourteenth embodiment the present invention provides apharmaceutical composition comprising a therapeutically effective amountof a compound, or combination of compounds of formula (I), (II), (III),(IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII) or (XIII), or apharmaceutically acceptable salt form, prodrug or stereoisomer thereof,and a pharmaceutically acceptable carrier.

For example, the present invention of the fourteenth embodiment providesa pharmaceutical composition comprising a therapeutically effectiveamount ofmethyl(1S)-1-[({(1R,3S,4S)-3-hydroxy-4-{[(2S)-2-(3-{[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate,or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof,and a pharmaceutically acceptable carrier.

For example, the present invention of the fourteenth embodiment providesa pharmaceutical composition comprising a therapeutically effectiveamount ofmethyl(1S)-1-[({(1S,3S,4S)-4-{[(2S)-2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate,or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof,and a pharmaceutically acceptable carrier.

For example, the present invention of the fourteenth embodiment providesa pharmaceutical composition comprising a therapeutically effectiveamount ofMethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-7-[2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate,or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof,and a pharmaceutically acceptable carrier.

For example, the present invention of the fourteenth embodiment providesa pharmaceutical composition comprising a therapeutically effectiveamount ofmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-bis(tert-butyl)-2,9,12-trioxo-5-[(phosphonooxy)methoxy]-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate,or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof,and a pharmaceutically acceptable carrier.

For example, the present invention of the fourteenth embodiment providesa pharmaceutical composition comprising a therapeutically effectiveamount ofdisodium(3S,5S,8S)-8-tert-butyl-3-((1S)-1-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-2-phenylethyl)-7,10-dioxo-5-(4-pyridin-2-ylbenzyl)-2,11-dioxa-6,9-diazadodec-1-ylphosphonate,or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof,and a pharmaceutically acceptable carrier.

In a fifteenth embodiment the present invention provides apharmaceutical composition comprising a therapeutically effective amountof a compound, or combination of compounds of formula (I), (II), (III),(IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII) or (XIII), or apharmaceutically acceptable salt form, prodrug or stereoisomer thereof,one, two, three, four, five or six second HIV protease inhibitors, and apharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S)-1-[({(1R,3S,4S)-3-hydroxy-4-{[(2S)-2-(3-benzyl-2-oxo-1-hydroxy-1-methylethyl)-2-pyridinyl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate,or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof,one, two, three, four, five or six second HIV protease inhibitors and apharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S)-1-[({(1S,3S,4S)-4-{[(2S)-2-(3-{[6-(1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate,or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof,one, two, three, four, five or six second HIV protease inhibitors and apharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,1-triazatetradec-1-ylcarbamate,a pharmaceutically acceptable salt, prodrug or stereoisomer thereof,one, two, three, four, five or six second HIV protease inhibitors and apharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-bis(tert-butyl)-2,9,12-trioxo-5-[(phosphonooxy)methoxy]-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate,or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof,one, two, three, four, five or six second HIV protease inhibitors and apharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofdisodium(3S,5S,8S)-8-tert-butyl-3-((1S)-1-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-2-phenylethyl)-7,10-dioxo-5-(4-pyridin-2-ylbenzyl)-2,11-dioxa-6,9-diazadodec-1-ylphosphonate,or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof,one, two, three, four, five or six second HIV protease inhibitors and apharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount of a compound, orcombination of compounds of formula (I), (II), (III), (IV), (V), (VI),(VII), (VIII), (IX), (X), (XI), (XII) or (XIII), or a pharmaceuticallyacceptable salt form, prodrug or stereoisomer thereof, one, two, three,four, five or six second HIV protease inhibitors selected from the groupconsisting of ritonavir, lopinavir, saquinavir, amprenavir,fosamprenavir, nelfinavir, tipranavir, indinavir, atazanavir, TMC-126,TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649,KNI-272, DPC-681, DPC-684 and GW640385X, and a pharmaceuticallyacceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S)-1-[({(1R,3S,4S)-3-hydroxy-4-{[(2S)-2-(3-{[6(1-hydroxy-1-methylethyl)-2-pyridinyl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate,or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof,one, two, three, four, five or six second HIV protease inhibitorsselected from the group consisting of ritonavir, lopinavir, saquinavir,amprenavir, fosamprenavir, nelfinavir, tipranavir, indinavir,atazanavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776),L-756423, RO0334649, KNI-272, DPC-681, DPC-684 and GW640385X, and apharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S)-1-[({(1S,3S,4S)-4-{[(2S)-2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two, three, four, five or six second HIV proteaseinhibitors selected from the group consisting of ritonavir, lopinavir,saquinavir, amprenavir, fosamprenavir, nelfinavir, tipranavir,indinavir, atazanavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147(AG1776), L-756423, RO0334649, KNI-272, DPC-681, DPC-684 and GW640385X,and a pharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two, three, four, five or six second HIV proteaseinhibitors selected from the group consisting of ritonavir, lopinavir,saquinavir, amprenavir, fosamprenavir, nelfinavir, tipranavir,indinavir, atazanavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147(AG1776), L-756423, RO0334649, KNI-272, DPC-681, DPC-684 and GW640385X,and a pharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10bis(tert-butyl)-2,9,12-trioxo-5-[(phosphonooxy)methoxy]-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two, three, four, five or six second HIV proteaseinhibitors selected from the group consisting of ritonavir, lopinavir,saquinavir, amprenavir, fosamprenavir, nelfinavir, tipranavir,indinavir, atazanavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147(AG1776), L-756423, RO0334649, KNI-272, DPC-681, DPC-684 and GW640385X,and a pharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofdisodium(3S,5S,8S)-8-tert-butyl-3-((1S)-1-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-2-phenylethyl)-7,10-dioxo-5-(4-pyridin-2-ylbenzyl)-2,11-dioxa-6,9-diazadodec-1-ylphosphonate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two, three, four, five or six second HIV proteaseinhibitors selected from the group consisting of ritonavir, lopinavir,saquinavir, amprenavir, fosamprenavir, nelfinavir, tipranavir,indinavir, atazanavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147(AG1776), L-756423, RO0334649, KNI-272, DPC-681, DPC-684 and GW640385X,and a pharmaceutically acceptable carrier.

In a sixteenth embodiment the present invention provides apharmaceutical composition comprising a therapeutically effective amountof a compound, or combination of compounds of formula (I), (II), (III),(IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII) or (XIII), or apharmaceutically acceptable salt form, stereoisomer, ester, salt of anester, prodrug, salt of a prodrug, or combination thereof, one, two,three, four, five or six HIV reverse transcriptase inhibitors, and apharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(15)-1-[({(1R,3S,4S)-3-hydroxy-4-{[(2S)-2-(3-{[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two, three, four, five or six HIV reverse transcriptaseinhibitors and a pharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S)-1-[({(1S,3S,4S)-4-{[(2S)-2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomer,ester thereof, one, two, three, four, five or six HIV reveresetranscriptase inhibitors and a pharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomer,ester thereof, one, two, three, four, five or six HIV reveresetranscriptase inhibitors and a pharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-bis(tert-butyl)-2,9,12-trioxo-5-[(phosphonooxy)methoxy]-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two, three, four, five or six HIV reverese transcriptaseinhibitors and a pharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofdisodium(3S,5S,8S)-8-tert-butyl-3-((1S)-1-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-2-phenylethyl)-7,10-dioxo-5-(4-pyridin-2-ylbenzyl)-2,11-dioxa-6,9-diazadodec-1-ylphosphonate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two, three, four, five or six HIV reverese transcriptaseinhibitors and a pharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount of a compound, orcombination of compounds of formula (I), (II), (III), (IV), (V), (VI),(VII), (VIII), (IX), (X), (XI), (XII) or (XIII), or a pharmaceuticalsacceptable salt form, prodrug or stereoisomer thereof, one, two, three,four, five or six HIV reverse transcriptase inhibitors selected from thegroup consisting of lamivudine, stavudine, zidovudine, abacavir,zalcitabine, didanosine, tenofovir, emtricitabine, amdoxovir,elvucitabine, alovudine, MIV-210, Racivir (±-FTC), D-D4FC (Reverset,DPC-817), SPD754, nevirapine, delavirdine, efavirenz, capravirine,emivirine, calanolide A, GW5634, BMS-56190 (DPC083), DPC-961, MIV-150,TMC-120 and TMC-125, and a pharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S)-1-[({(1R,3S,4S)-3-hydroxy-4-{[(2S)-2-(3-{[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two, three, four, five or six HIV reverse transcriptaseinhibitors selected from the group consisting of lamivudine, stavudine,zidovudine, abacavir, zalcitabine, didanosine, tenofovir, emtricitabine,amdoxovir, elvucitabine, alovudine, MIV-210, Racivir (±-FTC), D-D4FC(Reverset, DPC-817), SPD754, nevirapine, delavirdine, efavirenz,capravirine, emivirine, calanolide A, GW5634, BMS-56190 (DPC-083),DPC-961, MIV-150, TMC-120 and TMC-125, and a pharmaceutically acceptablecarrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S)-1-[({(1S,3S,4S)-4-{[(2S)-2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two, three, four, five or six HIV reverse transcriptaseinhibitors selected from the group consisting of lamivudine, stavudine,zidovudine, abacavir, zalcitabine, didanosine, tenofovir, emtricitabine,amdoxovir, elvucitabine, alovudine, MIV-210, Racivir (±-FTC), D-D4FC(Reverset, DPC-817), SPD754, nevirapine, delavirdine, efavirenz,capravirine, emivirine, calanolide A, GW5634, BMS-56190 (DPC-083),DPC-961, MIV-150, TMC-120 and TMC-125, and a pharmaceutically acceptablecarrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two, three, four, five or six HIV reverse transcriptaseinhibitors selected from the group consisting of lamivudine, stavudine,zidovudine, abacavir, zalcitabine, didanosine, tenofovir, emtricitabine,amdoxovir, elvucitabine, alovudine, MIV-210, Racivir (±-FTC), D-D4FC(Reverset, DPC-817), SPD754, nevirapine, delavirdine, efavirenz,capravirine, emivirine, calanolide A, GW5634, BMS-56190 (DPC-083),DPC-961, MIV-150, TMC-120 and TMC-125, and a pharmaceutically acceptablecarrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-bis(tert-butyl)-2,9,12-trioxo-5-[(phosphonooxy)methoxy]-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two, three, four, five or six HIV reverse transcriptaseinhibitors selected from the group consisting of lamivudine, stavudine,zidovudine, abacavir, zalcitabine, didanosine, tenofovir, emtricitabine,amdoxovir, elvucitabine, alovudine, MIV-210, Racivir (±-FTC), D-D4FC(Reverset, DPC-817), SPD754, nevirapine, delavirdine, efavirenz,capravirine, emivirine, calanolide A, GW5634, BMS-56190 (DPC-083),DPC-961, MIV-150, TMC-120 and TMC-125, and a pharmaceutically acceptablecarrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofdisodium(3S,5S,8S)-8-tert-butyl-3-((1S)-1-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-2-phenylethyl)-7,10-dioxo-5-(4-pyridin-2-ylbenzyl)-2,11-dioxa-6,9-diazadodec-1-ylphosphonate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two, three, four, five or six HIV reverse transcriptaseinhibitors selected from the group consisting of lamivudine, stavudine,zidovudine, abacavir, zalcitabine, didanosine, tenofovir, emtricitabine,amdoxovir, elvucitabine, alovudine, MIV-210, Racivir (±-FTC), D-D4FC(Reverset, DPC-817), SPD754, nevirapine, delavirdine, efavirenz,capravirine, emivirine, calanolide A, GW5634, BMS-56190 (DPC-083),DPC-961, MIV-150, TMC-120 and TMC-125, and a pharmaceutically acceptablecarrier.

In a seventeenth embodiment the present invention provides apharmaceutical composition comprising a therapeutically effective amountof a compound, or combination of compounds of formula (I), (II), (III),(IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII) or (XIII), or apharmaceutically acceptable salt form, prodrug or stereoisomer thereof,one, two, three, four, five or six HIV entry/fusion inhibitors and apharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S)-1-[({(1R,3S,4S)-3-hydroxy-4-{[(2S)-2-(3-{[6(1-hydroxy-1-methylethyl)-2-pyridinyl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two, three, four, five or six HIV entry/fusion inhibitorsand a pharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S)-1-[({(1S,3S,4S)-4-{[(2S)-2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two, three, four, five or six HIV entry/fusion inhibitorsand a pharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two, three, four, five or six HIV entry/fusion inhibitorsand a pharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-bis(tert-butyl)-2,9,12-trioxo-5-[(phosphonooxy)methoxy]-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two, three, four, five or six HIV entry/fusion inhibitorsand a pharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofdisodium(3S,5S,8S)-8-tert-butyl-3-((1S)-1-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-2-phenylethyl)-7,10-dioxo-5-(4-pyridin-2-ylbenzyl)-2,11-dioxa-6,9-diazadodec-1-ylphosphonate,or a pharmaceutically acceptable salt form or stereoisomer thereof, one,two, three, four, five or six HIV entry/fusion inhibitors and apharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount of a compound, orcombination of compounds of formula (I), (II), (III), (IV), (V), (VI),(VII), (VIII), (IX), (X), (XI), (XII) or (XIII), or a pharmaceuticallyacceptable salt form, prodrug or stereoisomer thereof, one, two, three,four, five or six HIV entry/fusion inhibitors selected from the groupconsisting of enfuvirtide (T-20), T-1249, PRO 2000, PRO 542, PRO 140,AMD-3100, BMS-806, FP21399, GW873140, Schering C (SCH-C), Schering D(SCH-D), TNX-355 and UK-427857, and a pharmaceutically acceptablecarrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S)-1-[({(1R,3S,4S)-3-hydroxy-4-{[(2S)-2-(3-{[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two, three, four, five or six HIV entry/fusion inhibitorsselected from the group consisting of enfuvirtide (T-20), T-1249, PRO2000, PRO 542, PRO 140, AMD-3100, BMS-806, FP21399, GW873140, Schering C(SCH-C), Schering D (SCH-D), TNX-355 and UK-427857, and apharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S)-1-[({(1S,3S,4S)-4-{[(2S)-2-(2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two, three, four, five or six HIV entry/fusion inhibitorsselected from the group consisting of enfuvirtide (T-20), T-1249, PRO2000, PRO 542, PRO 140, AMD-3100, BMS-806, FP21399, GW873140, Schering C(SCH-C), Schering D (SCH-D), TNX-355 and UK-427857, and apharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofMethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two, three, four, five or six HIV entry/fusion inhibitorsselected from the group consisting of enfuvirtide (T-20), T-1249, PRO2000, PRO 542, PRO 140, AMD-3100, BMS-806, FP21399, GW873140, Schering C(SCH-C), Schering D (SCH-D), TNX-355 and UK-427857, and apharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-bis(tert-butyl)-2,9,12-trioxo-5-[(phosphonooxy)methoxy]-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two, three, four, five or six HIV entry/fusion inhibitorsselected from the group consisting of enfuvirtide (T-20), T-1249, PRO2000, PRO 542, PRO 140, AMD-3 100, BMS-806, FP21399, GW873140, ScheringC (SCH-C), Schering D (SCH-D), TNX-355 and UK-427857, and apharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofdisodium(3S,5S,8S)-8-tert-butyl-3-((1S)-1-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-2-phenylethyl)-7,10-dioxo-5-(4-pyridin-2-ylbenzyl)-2,11-dioxa-6,9-diazadodec-1-ylphosphonate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two, three, four, five or six HIV entry/fusion inhibitorsselected from the group consisting of enfuvirtide (T-20), T-1249, PRO2000, PRO 542, PRO 140, AMD-3100, BMS-806, FP21399, GW873140, Schering C(SCH-C), Schering D (SCH-D), TNX-355 and UK-427857, and apharmaceutically acceptable carrier.

In an eighteenth embodiment the present invention provides apharmaceutical composition comprising a therapeutically effective amountof a compound, or combination of compounds of formula (I), (II), (III),(IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII) or (XIII), or apharmaceutically acceptable salt form, prodrug or stereoisomer thereof,one, two, three, four, five or six HIV integrase inhibitors and apharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S)-1-[({(1R,3S,4S)-3-hydroxy-4-{[(2S)-2-(3-{[(6-(1-hydroxy-1-methylethyl)-2-pyridinyl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two, three, four, five or six HIV integrase inhibitors anda pharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S)-1-[({(1S,3S,4S)-4-{[(2S)-2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two, three, four, five or six HIV integrase inhibitors anda pharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount of a compound, orcombination of compounds of formula (I), (II), (III), (IV), (V), (VI),(VII), (VIII), (IX), (X), (XI), (XII) or (XIII), or a pharmaceuticallyacceptable salt form, prodrug or stereoisomer thereof, one, two, threeor four HIV integrase inhibitors selected from the group consisting ofS-1360, zintevir (AR-177), L-870812 and L-870810, and a pharmaceuticallyacceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S)-1-[({(1R,3S,4S)-3-hydroxy-4-{[(2S)-2-(3-{[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two, three or four HIV integrase inhibitors selected fromthe group consisting of S-1360, zintevir (AR-177), L-870812 andL-870810, and a pharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S)-1-[({(1S,3S,4S)-4-{[(2S)-2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two, three or four HIV integrase inhibitors selected fromthe group consisting of S-1360, zintevir (AR-177), L-870812 andL-870810, and a pharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate,a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two, three or four HIV integrase inhibitors selected fromthe group consisting of S-1360, zintevir (AR-177), L-870812 andL-870810, and a pharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-bis(tert-butyl)-2,9,12-trioxo-5-[(phosphonooxy)methoxy]-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two, three or four HIV integrase inhibitors selected fromthe group consisting of S-1360, zintevir (AR-177), L-870812 andL-870810, and a pharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofdisodium(3S,5S,8S)-8-tert-butyl-3-((1S)-1-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-2-phenylethyl)-7,10-dioxo-5-(4-pyridin-2-ylbenzyl)-2,11-dioxa-6,9-diazadodec-1-ylphosphonate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two, three or four HIV integrase inhibitors selected fromthe group consisting of S-1360, zintevir (AR-177), L-870812 andL-870810, and a pharmaceutically acceptable carrier.

In a nineteenth embodiment the present invention provides apharmaceutical composition comprising a therapeutically effective amountof a compound, or combination of compounds of formula (I), (II), (III),(IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII) or (XIII), or apharmaceutically acceptable salt form, prodrug or stereoisomer thereof,one, two, three, four, five or six HIV budding/maturation inhibitors anda pharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S)-1-[({(1R,3S,4S)-3-hydroxy-4-{[(2S)-2-(3-{[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two, three, four, five or six HIV budding/maturationinhibitors and a pharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S)-1-[({(1S,3S,4S)-4-{[(2S)-2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two, three, four, five or six HIV budding/maturationinhibitors and a pharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two, three, four, five or six HIV budding/maturationinhibitors and a pharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-bis(tert-butyl)-2,9,12-trioxo-5-[(phosphonooxy)methoxy]-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two, three, four, five or six HIV budding/maturationinhibitors and a pharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofdisodium(3S,5S,8S)-8-tert-butyl-3-((1S)-1-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-2-phenylethyl)-7,10-dioxo-5-(4-pyridin-2-ylbenzyl)-2,11-dioxa-6,9-diazadodec-1-ylphosphonate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two, three, four, five or six HIV budding/maturationinhibitors and a pharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount of a compound, orcombination of compounds of formula (I), (II), (III), (IV), (V), (VI),(VII), (VIII), (IX), (X), (XI), (XII) or (XIII), or a pharmaceuticallyacceptable salt form, prodrug or stereoisomer thereof, PA-457, and apharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S)-1-[({(1R,3S,4S)-3-hydroxy-4-{[(2S)-2-(3-{[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, PA-457, and a pharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S)-1-[({(1S,3S,4S)-4-{[(2S)-2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate, or apharmaceutically acceptable salt form, prodrug or stereoisomer thereof,PA-457, and a pharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, PA-457, and a pharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-bis(tert-butyl)-2,9,12-trioxo-5-[(phosphonooxy)methoxy]-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, PA-457, and a pharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofdisodium(3S,5S,8S)-8-tert-butyl-3-((1S)-1-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-2-phenylethyl)-7,10-dioxo-5-(4-pyridin-2-ylbenzyl)-2,11-dioxa-6,9-diazadodec-1-ylphosphonate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, PA-457, and a pharmaceutically acceptable carrier.

In a twentieth embodiment the present invention provides apharmaceutical composition comprising a therapeutically effective amountof a compound, or combination of compounds of formula (I), (II), (III),(IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII) or (XIII), or apharmaceutically acceptable salt form, prodrug or stereoisomer thereof,one, two or three second HIV protease inhibitor, one, two or three HIVreverese transcriptase inhibitor and a pharmaceutically acceptablecarrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S)-1-[({(1R,3S,4S)-3-hydroxy-4-{[(2S)-2-(3-{[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two or three second HIV protease inhibitor, one, two orthree HIV reverse transcriptase inhibitor and a pharmaceuticallyacceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S)-1-[({(1S,3S,4S)-4-{[(2S)-2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate, or apharmaceutically acceptable salt form, prodrug or stereoisomer thereof,one, two or three second HIV protease inhibitor, one, two or three HIVreverse transcriptase inhibitor and a pharmaceutically acceptablecarrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two or three second HIV protease inhibitor, one, two orthree HIV reverse transcriptase inhibitor and a pharmaceuticallyacceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-bis(tert-butyl)-2,9,12-trioxo-5-[(phosphonooxy)methoxy]-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two or three second HIV protease inhibitor, one, two orthree HIV reverse transcriptase inhibitor and a pharmaceuticallyacceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofdisodium(3S,5S,8S)-8-tert-butyl-3-((1S)-1-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-2-phenylethyl)-7,10-dioxo-5-(4-pyridin-2-ylbenzyl)-2,11-dioxa-6,9-diazadodec-1-ylphosphonate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two or three second HIV protease inhibitor, one, two orthree HIV reverse transcriptase inhibitor and a pharmaceuticallyacceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount of a compound, orcombination of compounds of formulae (I), (II), (III), (IV), (V), (VI),(VII), (VIII), (IX), (X), (XI), (XII) or (XIII), or a pharmaceuticallyacceptable salt form, prodrug or stereoisomer thereof, one, two or threesecond HIV protease inhibitors selected from the group consisting ofritonavir, lopinavir, saquinavir, amprenavir, fosamprenavir, nelfinavir,tipranavir, indinavir, atazanavir, TMC-126, TMC-114, mozenavir(DMP-450), JE-2147 (AG1776), L-756423, RO0334649, KNI-272, DPC-681,DPC-684 and GW640385X, one, two or three HIV reverse transcriptaseinhibitors selected from the group consisting of lamivudine, stavudine,zidovudine, abacavir, zalcitabine, didanosine, tenofovir, emtricitabine,amdoxovir, elvucitabine, alovudine, MIV-210, Racivir (±-FTC), D-D4FC(Reverset, DPC-817), SPD754, nevirapine, delavirdine, efavirenz,capravirine, emivirine, calanolide A, GW5634, BMS-56190 (DPC-083),DPC-961, MIV-150, TMC-120 and TMC-125, and a pharmaceutical acceptablecarrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S)-1-[({(1R,3S,4S)-3-hydroxy-4-{[(2S)-2-(3-{[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two or three second HIV protease inhibitors selected fromthe group consisting of ritonavir, lopinavir, saquinavir, amprenavir,fosamprenavir, nelfinavir, tipranavir, indinavir, atazanavir, TMC-126,TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649,KNI-272, DPC-681, DPC-684 and GW640385X, one, two or three HIV reversetranscriptase inhibitors selected from the group consisting oflamivudine, stavudine, zidovudine, abacavir, zalcitabine, didanosine,tenofovir, emtricitabine, amdoxovir, elvucitabine, alovudine, MIV-210,Racivir (±-FTC), D-D4FC (Reverset, DPC-817), SPD754, nevirapine,delavirdine, efavirenz, capravirine, emivirine, calanolide A, GW5634,BMS-56190 (DPC-083), DPC-961, MIV-150, TMC-120 and TMC-125, and apharmaceutical acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S)-1-[({(1S,3S,4S)-4-{[(2S)-2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate, or apharmaceutically acceptable salt form, prodrug or stereoisomer thereof,one, two or three second HIV protease inhibitors selected from the groupconsisting of ritonavir, lopinavir, saquinavir, amprenavir,fosamprenavir, nelfinavir, tipranavir, indinavir, atazanavir, TMC-126,TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649,KNI-272, DPC-681, DPC-684 and GW640385X, one, two or three HIV reversetranscriptase inhibitors selected from the group consisting oflamivudine, stavudine, zidovudine, abacavir, zalcitabine, didanosine,tenofovir, emtricitabine, amdoxovir, elvucitabine, alovudine, MIV-210,Racivir (±-FTC), D-D4FC (Reverset, DPC-817), SPD754, nevirapine,delavirdine, efavirenz, capravirine, emivirine, calanolide A, GW5634,BMS-56190 (DPC-083), DPC-961, MIV-150, TMC-120 and TMC-125, and apharmaceutical acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two or three second HIV protease inhibitors selected fromthe group consisting of ritonavir, lopinavir, saquinavir, amprenavir,fosamprenavir, nelfinavir, tipranavir, indinavir, atazanavir, TMC-126,TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649,KNI-272, DPC-681, DPC-684 and GW640385X, one, two or three HIV reversetranscriptase inhibitors selected from the group consisting oflamivudine, stavudine, zidovudine, abacavir, zalcitabine, didanosine,tenofovir, emtricitabine, amdoxovir, elvucitabine, alovudine, MIV-210,Racivir (±-FTC), D-D4FC (Reverset, DPC-817), SPD754, nevirapine,delavirdine, efavirenz, capravirine, emivirine, calanolide A, GW5634,BMS-56190 (DPC-083), DPC-961, MIV-150, TMC-120 and TMC-125, and apharmaceutical acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-bis(tert-butyl)-2,9,12-trioxo-5-[(phosphonooxy)methoxy]-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two or three second HIV protease inhibitors selected fromthe group consisting of ritonavir, lopinavir, saquinavir, amprenavir,fosamprenavir, nelfinavir, tipranavir, indinavir, atazanavir, TMC-126,TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649,KNI-272, DPC-681, DPC-684 and GW640385X, one, two or three HIV reversetranscriptase inhibitors selected from the group consisting oflamivudine, stavudine, zidovudine, abacavir, zalcitabine, didanosine,tenofovir, emtricitabine, amdoxovir, elvucitabine, alovudine, MIV-210,Racivir (±-FTC), D-D4FC (Reverset, DPC-817), SPD754, nevirapine,delavirdine, efavirenz, capravirine, emivirine, calanolide A, GW5634,BMS-56190 (DPC-083), DPC-961, MIV-150, TMC-120 and TMC-125, and apharmaceutical acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofdisodium(3S,5S,8S)-8-tert-butyl-3-((1S)-1-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-2-phenylethyl)-7,10-dioxo-5-(4-pyridin-2-ylbenzyl)-2,11-dioxa-6,9-diazadodec-1-ylphosphonate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two or three second HIV protease inhibitors selected fromthe group consisting of ritonavir, lopinavir, saquinavir, amprenavir,fosamprenavir, nelfinavir, tipranavir, indinavir, atazanavir, TMC-126,TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649,KNI-272, DPC-681, DPC-684 and GW640385X, one, two or three HIV reversetranscriptase inhibitors selected from the group consisting oflamivudine, stavudine, zidovudine, abacavir, zalcitabine, didanosine,tenofovir, emtricitabine, amdoxovir, elvucitabine, alovudine, MIV-210,Racivir (±-FTC), D-D4FC (Reverset, DPC-817), SPD754, nevirapine,delavirdine, efavirenz, capravirine, emivirine, calanolide A, GW5634,BMS-56190 (DPC-083), DPC-961, MIV-150, TMC-120 and TMC-125, and apharmaceutical acceptable carrier.

In a twenty-first embodiment the present invention provides apharmaceutical composition comprising a therapeutically effective amountof a compound, or combination of compounds of formula (I), (II), (III),(IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII) or (XIII), or apharmaceutically acceptable salt form, prodrug or stereoisomer thereof,one, two or three second HIV protease inhibitor, one, two or three HIVentry/fusion inhibitor and a pharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S)-1-[({(1R,3S,4S)-3-hydroxy-4-{[(2S)-2-(3-{[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two or three second HIV protease inhibitor, one, two orthree HIV entry/fusion inhibitor and a pharmaceutically acceptablecarrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S)-1-[({(1S,3S,4S)-4-{[(2S)-2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate, or apharmaceutically acceptable salt form, prodrug or stereoisomer thereof,one, two or three second HIV protease inhibitor, one, two or three HIVentry/fusion inhibitor and a pharmaceutically acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two or three second HIV protease inhibitor, one, two orthree HIV entry/fusion inhibitor and a pharmaceutically acceptablecarrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,1-bis(tert-butyl)-2,9,12-trioxo-5-[(phosphonooxy)methoxy]-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two or three second HIV protease inhibitor, one, two orthree HIV entry/fusion inhibitor and a pharmaceutically acceptablecarrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofdisodium(3S,5S,8S)-8-tert-butyl-3-((1S)-1-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-2-phenylethyl)-7,10-dioxo-5-(4-pyridin-2-ylbenzyl)-2,11-dioxa-6,9-diazadodec-1-ylphosphonate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two or three second HIV protease inhibitor, one, two orthree HIV entry/fusion inhibitor and a pharmaceutically acceptablecarrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount of a compound, orcombination of compounds of formulae (I), (II), (III), (IV), (V), (VI),(VII), (VIII), (IX), (X), (XI), (XII) or (XIII), or a pharmaceuticallyacceptable salt form, prodrug or stereoisomer thereof, one, two orthree, second HIV protease inhibitors selected from the group consistingof ritonavir, lopinavir, saquinavir, amprenavir, fosamprenavir,nelfinavir, tipranavir, indinavir, atazanavir, TMC-126, TMC-114,mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649, KNI-272,DPC-681, DPC-684 and GW640385X, one, two or three HIV entry/fusioninhibitors selected from the group consisting of enfuvirtide (T-20),T-1249, PRO 2000, PRO 542, PRO 140, AMD-3100, BMS-806, FP21399,GW873140, Schering C (SCH-C), Schering D (SCH-D), TNX-355 and UK-427857,and a pharmaceutical acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S)-1-[({(1R,3S,4S)-3-hydroxy-4-{[(2S)-2-(3-{[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two or three second HIV protease inhibitors selected fromthe group consisting of ritonavir, lopinavir, saquinavir, amprenavir,fosamprenavir, nelfinavir, tipranavir, indinavir, atazanavir, TMC-126,TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649,KNI-272, DPC-681, DPC-684 and GW640385X, one, two or three HIVentry/fusion inhibitors selected from the group consisting ofenfuvirtide (T-20), T-1249, PRO 2000, PRO 542, PRO 140, AMD-3100,BMS-806, FP21399, GW873140, Schering C (SCH-C), Schering D (SCH-D),TNX-355 and UK-427857, and a pharmaceutical acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S)-1-[({(1S,3S,4S)-4-{[(2S)-2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate, or apharmaceutically acceptable salt form, prodrug or stereoisomer thereof,one, two or three second HIV protease inhibitors selected from the groupconsisting of ritonavir, lopinavir, saquinavir, amprenavir,fosamprenavir, nelfinavir, tipranavir, indinavir, atazanavir, TMC-126,TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649,KNI-272, DPC-681, DPC-684 and GW640385X, one, two or three HIVentry/fusion inhibitors selected from the group consisting ofenfuvirtide (T-20), T-1249, PRO 2000, PRO 542, PRO 140, AMD-3100,BMS-806, FP21399, GW873140, Schering C (SCH-C), Schering D (SCH-D),TNX-355 and UK-427857, and a pharmaceutical acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two or three second HIV protease inhibitors selected fromthe group consisting of ritonavir, lopinavir, saquinavir, amprenavir,fosamprenavir, nelfinavir, tipranavir, indinavir, atazanavir, TMC-126,TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649,KNI-272, DPC-681, DPC-684 and GW640385X, one, two or three HIVentry/fusion inhibitors selected from the group consisting ofenfuvirtide (T-20), T-1249, PRO 2000, PRO 542, PRO 140, AMD3100,BMS-806, FP21399, GW873140, Schering C (SCH-C), Schering D (SCH-D),TNX-355 and UK-427857, and a pharmaceutical acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-bis(tert-butyl)-2,9,12-trioxo-5-[(phosphonooxy)methoxy]-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two or three second HIV protease inhibitors selected fromthe group consisting of ritonavir, lopinavir, saquinavir, amprenavir,fosamprenavir, nelfinavir, tipranavir, indinavir, atazanavir, TMC-126,TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649,KNI-272, DPC-681, DPC-684 and GW640385X, one, two or three HIVentry/fusion inhibitors selected from the group consisting ofenfuvirtide (T-20), T-1249, PRO 2000, PRO 542, PRO 140, AMD-3100,BMS-806, FP21399, GW873140, Schering C (SCH-C), Schering D (SCH-D),TNX-355 and UK-427857, and a pharmaceutical acceptable carrier.

For example, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount ofdisodium(3S,5S,8S)-8-tert-butyl-3-((1S)-1-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-2-phenylethyl)-7,10-dioxo-5-(4-pyridin-2-ylbenzyl)-2,11-dioxa-6,9-diazadodec-1-ylphosphonate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof, one, two or three second HIV protease inhibitors selected fromthe group consisting of ritonavir, lopinavir, saquinavir, amprenavir,fosamprenavir, nelfinavir, tipranavir, indinavir, atazanavir, TMC-126,TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649,KNI-272, DPC-681, DPC-684 and GW640385X, one, two or three HIVentry/fusion inhibitors selected from the group consisting ofenfuvirtide (T-20), T-1249, PRO 2000, PRO 542, PRO 140, AMD3100,BMS-806, FP21399, GW873140, Schering C (SCH-C), Schering D (SCH-D),TNX-355 and UK-427857, and a pharmaceutical acceptable carrier.

In a twenty-second embodiment the present invention provides a method ofinhibiting the replication of an HIV virus comprising contacting saidvirus with a therapeutically effective amount of a compound orcombination of compounds of formula (I), (II), (III), (IV), (V), (VI),(VII), (VIII), (IX), (X), (XI), (XII) or (XIII), or a pharmaceuticallyacceptable salt form, prodrug or stereoisomer thereof.

For example, the present invention provides a method of inhibiting thereplication of an HIV virus comprising contacting said virus with atherapeutically effective amount ofmethyl(1S)-1-[({(1R,3S,4S)-3-hydroxy-4-{[(2S)-2-(3-{[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof.

For example, the present invention provides a method of inhibiting thereplication of an HIV virus comprising contacting said virus with atherapeutically effective amount ofmethyl(1S)-1-[({(1S,3S,4S)-4-{[(2S)-2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate, or apharmaceutically acceptable salt form, prodrug or stereoisomer thereof.

For example, the present invention provides a method of inhibiting thereplication of an HIV virus comprising contacting said virus with atherapeutically effective amount ofmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof.

For example, the present invention provides a method of inhibiting thereplication of an HIV virus comprising contacting said virus with atherapeutically effective amount ofmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-bis(tert-butyl)-2,9,12-trioxo-5-[(phosphonooxy)methoxy]-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof.

For example, the present invention provides a method of inhibiting thereplication of an HIV virus comprising contacting said virus with atherapeutically effective amount ofdisodium(3S,5S,8S)-8-tert-butyl-3-((1S)-1-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-2-phenylethyl)-7,10-dioxo-5-(4-pyridin-2-ylbenzyl)-2,11-dioxa-6,9-diazadodec-1-ylphosphonate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof.

In a twenty-third embodiment the present invention provides a method ofinhibiting HIV protease comprising contacting said HIV protease with atherapeutically effective amount of a compound or combination ofcompounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII),(IX), (X), (XI), (XII) or (XIII), or a pharmaceutically acceptable saltform, prodrug or streoisomer thereof.

For example, the present invention provides a method of inhibiting HIVprotease comprising contacting said HIV protease with a therapeuticallyeffective amount ofmethyl(1S)-1-[({(1R,3S,4S)-3-hydroxy-4-{[(2S)-2-(3-{[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate, or apharmaceutically acceptable salt form, prodrug or stereoisomer thereof.

For example, the present invention provides a method of inhibiting HIVprotease comprising contacting said HIV protease with a therapeuticallyeffective amount ofmethyl(1S)-1-[({(1S,3S,4S)-4-{[(2S)-2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate, or a pharmaceutically acceptable saltform, prodrug or stereoisomer thereof.

For example, the present invention provides a method of inhibiting HIVprotease comprising contacting said HIV protease with a therapeuticallyeffective amount ofmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof.

For example, the present invention provides a method of inhibiting HIVprotease comprising contacting said HIV protease with a therapeuticallyeffective amount ofmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-bis(tert-butyl)-2,9,12-trioxo-5-[(phosphonooxy)methoxy]-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof.

For example, the present invention provides a method of inhibiting HIVprotease comprising contacting said HIV protease with a therapeuticallyeffective amount ofdisodium(3S,5S,8S)-8-tert-butyl-3-((1S)-1-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-2-phenylethyl)-7,10-dioxo-5-(4-pyridin-2-ylbenzyl)-2,11-dioxa-6,9-diazadodec-1-ylphosphonate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof.

In a twenty-fourth embodiment the present invention provides a method oftreating or preventing an HIV infection comprising administering to apatient in need of such treatment a therapeutically effective amount ofa compound or combination of compounds of formula (I), (II), (III),(IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII) or (XIII), or apharmaceutically acceptable salt form, prodrug or streoisomer thereof.

For example, the present invention provides a method of treating orpreventing an HIV infection comprising administering to a patient inneed of such treatment a therapeutically effective amount ofmethyl(1S)-1-[({(1R,3S,4S)-3-hydroxy-4-{[(2S)-2-(3-{[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof.

For example, the present invention provides a method of treating orpreventing an HIV infection comprising administering to a patient inneed of such treatment a therapeutically effective amount ofmethyl(1S)-1-[({(1S,3S,4S)-4-{[(2S)-2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate, or apharmaceutically acceptable salt form, prodrug or stereoisomer thereof.

For example, the present invention provides a method of treating orpreventing an HIV infection comprising administering to a patient inneed of such treatment a therapeutically effective amount ofmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof.

For example, the present invention provides a method of treating orpreventing an HIV infection comprising administering to a patient inneed of such treatment a therapeutically effective amount ofmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-bis(tert-butyl)-2,9,12-trioxo-5-[(phosphonooxy)methoxy]-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof.

For example, the present invention provides a method of treating orpreventing an HIV infection comprising administering to a patient inneed of such treatment a therapeutically effective amount ofdisodium(3S,5S,8S)-8-tert-butyl-3-((1S)-1-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-2-phenylethyl)-7,10-dioxo-5-(4-pyridin-2-ylbenzyl)-2,11-dioxa-6,9-diazadodec-1-ylphosphonate,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof.

In a twenty-fifth embodiment the present invention provides a method ofinhibiting the replication of an HIV virus comprising contacting saidvirus with any one of the pharmaceutical compositions disclosedhereinabove.

In a twenty-sixth embodiment the present invention provides a method ofinhibiting HIV protease comprising contacting said HIV protease with anyone of the pharmaceutical compositions disclosed hereinabove.

In a twenty-seventh embodiment the present invention provides a methodof treating or preventing an HIV infection comprising administering to apatient in need of such treatment any one of the pharmaceuticalcompositions disclosed hereinabove.

In a twenty-eighth embodiment the present invention provides an HIVprotease inhibiting compound comprising a substituent of the formula(XIV):

-   X is O, S or NH;-   Y is O, S or NH;-   B is H or —CH₂R⁹;-   L is —C(═O), —C(═S), —C(═NH) or —S(O)₂;-   R⁷ is —N(R_(b))C(O)OR_(a), alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, heterocycle, aryl or heteroaryl; wherein the alkyl,    alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl and    heteroaryl are independently substituted with 0, 1 or 2 substituents    independently selected from the group consisting of halo, —OR_(a),    —OC(O)R_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —NR_(a)R_(b),    —N(R_(b))C(O)R_(a), —N(R_(b))C(O)OR_(a), —N(R_(a))C(═N)NR_(a)R_(b),    —N(R_(a))C(O)NR_(a)R_(b), —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(7a);-   R^(7a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(7a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R⁹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R⁹ is substituted with 0, 1,    2 or 3 substituents independently selected from the group consisting    of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro, oxo,    —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))SO₂R_(a),    —N(R_(b))SO₂NR_(a)R_(b), —N(R_(b))C(O)NR_(a)R_(b),    —N(R_(b))C(O)OR_(a), —C(O)R_(a), —C(O)NR_(a)R_(b), —C(O)OR_(a),    haloalkyl, nitroalkyl, cyanoalkyl, formylalkyl, -alkylOR_(a),    -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)OR_(a), -alkylN(R_(b))SO₂NR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkylC(O)R_(a),    -alkylC(O)NR_(a)R_(b) and R^(9a);-   R^(9a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(9a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹⁰ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R¹⁰ is substituted with 0,    1, 2 or 3 substituents independently selected from the group    consisting of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro,    oxo, —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))SO₂R_(a),    —N(R_(b))SO₂NR_(a)R_(b), —N(R_(b))C(O)NR_(a)R_(b),    —N(R_(b))C(O)OR_(a), —C(O)R_(a), —C(O)NR_(a)R_(b), —C(O)OR_(a),    haloalkyl, nitroalkyl, cynaoalkyl, formylalkyl, -alkylOR_(a),    -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)OR_(a), -alkylN(R_(b))SO₂NR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkylC(O)R_(a),    -alkylC(O)NR_(a)R_(b) and R^(10a);-   R^(10a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or    heteroaryl; wherein each R^(10a) is substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R¹¹ is substituted with 0,    1, 2 or 3 substituents independently selected from the group    consisting of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro,    oxo, —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))SO₂R_(a),    —N(R_(b))SO₂NR_(a)R_(b), —N(R_(b))C(O)NR_(a)R_(b),    —N(R_(b))C(O)OR_(a), —C(O)R_(a), —C(O)NR_(a)R_(b), —C(O)OR_(a),    haloalkyl, nitroalkyl, cynaoalkyl, formylalkyl, -alkylOR_(a),    -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)OR_(a), -alkylN(R_(b))SO₂NR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkylC(O)R_(a),    -alkylC(O)NR_(a)R_(b) and R^(11a);-   R^(11a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or    heteroaryl; wherein each R^(11a) is substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R¹² is alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl or    cycloalkenylalkyl; wherein each R¹² is substituted with 0, 1 or 2    substituents independently selected from the group consisting of    hydroxy, alkoxy and halo;-   R¹³ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R¹³ is substituted with 0,    1, 2 or 3 substituents independently selected from the group    consisting of alkyl, alkenyl, alkynyl, cyano, halo, nitro, oxo,    —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))C(O)OR_(a),    —C(O)NR_(a)R_(b), —C(O)OR_(a), haloalkyl, nitroalkyl, cynaoalkyl,    -alkylOR_(a), -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkyl-C(O)NR_(a)R_(b) and    R^(13a);-   R^(13a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or    heteroaryl; wherein each R^(13a) is substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R_(a) and R_(b) at each occurrence are independently selected from    the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    cycloalkyl, aryl, heteroaryl and heterocycle; wherein each R_(a) and    R_(b), at each occurrence, is independently substituted with 0, 1, 2    or 3 substituents independently selected from the group consisting    of cyano, nitro, halo, oxo, alkyl, alkenyl, alkynyl, hydroxy,    alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and R_(c);-   alternatively, R_(a) and R_(b), together with the nitrogen atom to    which they are attached, form a ring selected from the group    consisting of heteroaryl and heterocycle; wherein each of the    heteroaryl and heterocycle is independently substituted with 0, 1, 2    or 3 substituents independently selected from the group consisting    of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo,    hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),    —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, formylalkyl,    nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH₂,    -alkylN(H)(alkyl), -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂,    -alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH,    -alkylC(O)Oalkyl, -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl),    -alkylC(O)N(alkyl)₂ and R_(c);-   R_(c) is aryl, heteroaryl or heterocycle; wherein each R_(c) is    independently substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of halo, nitro,    oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, -S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkyl-NH₂, -alkyl-N(H)(alkyl), -alkyl-N(alkyl)₂,    -alkyl-N(H)C(O)NH₂, -alkyl-N(H)C(O)N(H)(alkyl),    -alkyl-N(H)C(O)N(alkyl)₂, -alkyl-C(O)OH, -alkyl-C(O)Oalkyl,    -alkyl-C(O)NH₂, -alkyl-C(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂; and-   n is 1 or 2.

For example, the present invention provides a compound comprising asubstituent of formula (XIV) wherein L is —C(═O) or —C(═S), X is O, Y isO; and B, R⁷, R^(7a), R⁹, R⁹, R¹⁰, R^(10a), R¹¹, R^(11a), R¹², R¹³,R^(13a), R_(a), R_(b), R_(c) and n are as defined in formula (XIV).

For example, the present invention provides a compound comprising asubstituent of formula (XIV) wherein L is —C(═O) or —C(═S), X is O, Y isO, R⁷ is alkyl; and B, R^(7a), R⁹, R^(9a), R¹⁰, R^(10a), R¹¹, R^(11a),R¹², R¹³, R^(13a), R_(a), R_(b), R_(c), n and substituents of R⁷ are asdefined in formula (XIV).

For example, the present invention provides a compound comprising asubstituent of formula (XIV) wherein L is —C(═O) or —C(═S), X is O, Y isO, R⁷ is alkyl, R¹² is alkyl, and B, R^(7a), R⁹, R^(9a), R¹⁰, R^(10a),R¹¹, R^(11a), R¹³, R^(13a), R_(a), R_(b), R_(c) n and substituents of R⁷are as defined in formula (XIV).

For example, the present invention provides a compound comprising asubstituent of formula (XIV) wherein L is —C(═O) or —C(═S), X is O, Y isO, R⁷ is alkyl, R¹² is alkyl, R⁹, R¹⁰, R¹¹ and R¹³ are independentlyselected from the group consisting of aryl and heteroaryl; and B, R⁷,R^(7a), R^(9a), R¹⁰ , R^(10a), R^(11a), R^(13a), R_(a), R_(b), R_(c) nand substituents of R⁷, R⁹, R¹⁰, R¹¹ and R¹³, are as defined in formula(XIV).

For example, the present invention provides a compound comprising asubstituent of formula (XIV) wherein L is —C(═O) or —C(═S), X is O, Y isO, R⁷ is alkyl, R¹² is alkyl and R⁹, R¹⁰, R¹¹ and R¹³ are independentlyselected from the group consisting of thienyl, furanyl, pyrrolyl,thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl,isoquinolinyl, quinolinyl, pyridyl, phenyl, pyridoimidazolyl,benzimiazolyl, benzothienyl, benzthiazolyl and indazolyl; and B, R⁷,R^(7a), R^(9a), R^(10a), R^(11a), R^(13a), R_(a), R_(b), R_(c) n andsubstituents of R⁷, R⁹, R¹⁰, R¹¹ and R¹³, are as defined in formula(XIV).

For example, the present invention provides a compound comprising asubstituent of formula (XIV) wherein L is —C(═O) or —C(═S), X is O, Y isO, R⁷ is C1, C2, C3, C4 or C5 alkyl, R¹² is alkyl, and R⁹, R¹⁰, R¹¹ andR¹³ are independently selected from the group consisting of thienyl,furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl,isothiazolyl, isoxazolyl, isoquinolinyl, quinolinyl, pyridyl, phenyl,pyridoimidazolyl, benzimiazolyl, benzothienyl, benzthiazolyl andindazolyl, and B, R⁷, R^(7a), R^(9a), R^(10a), R^(11a), R^(13a), R_(a),R_(b), R_(c) n and substituents of R⁷, R⁹, R¹⁰, R¹¹ and R¹³, are asdefined in formula (XIV).

For example, the present invention provides a compound comprising asubstituent of formula (XIV) wherein L is —C(═O) or —C(═S), X is O, Y isO, R⁷ is tert-butyl, 1-methylpropyl or isopropyl, R¹² is alkyl, R⁹, R¹⁰,R¹¹ and R¹³ are independently selected from the group consisting ofthienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl,isothiazolyl, isoxazolyl, isoquinolinyl, quinolinyl, pyridyl, phenyl,pyridoimidazolyl, benzimiazolyl, benzothienyl, benzthiazolyl andindazolyl; and B, R⁷, R^(7a), R^(9a), R^(10a), R^(11a), R^(13a), R_(a),R_(b), R_(c) n and substituents of R⁷, R⁹, R¹⁰, R¹¹ and R¹³, are asdefined in formula (XIV).

For example, the present invention provides a compound comprising asubstituent of formula (XIV) wherein L is —C(═O) or —C(═S), X is O, Y isO, R⁷ is tert-butyl, 1-methylpropyl or isopropyl, R¹² is methyl orethyl, R⁹, R¹⁰, R¹¹ and R¹³ are independently selected from the groupconsisting of thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl,imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, isoquinolinyl,quinolinyl, pyridyl, phenyl, pyridoimidazolyl, benzimiazolyl,benzothienyl, benzthiazolyl and indazolyl; and B, R⁷, R^(7a), R^(9a),R^(10a), R^(11a), R^(13a), R_(a), R_(b), R_(c) n and substituents of R⁷,R⁹, R¹⁰, R¹¹ and R¹³, are as defined in formula (XIV).

HIV protease inhibiting compounds comprising a substituent of theformula (XIV) can be prepared by coupling a suitable intermediate orprecursor molecule having an amino group (—NH₂ or —NHR* wherein R* isalkyl), a hydroxy group (—OH) or a thiol group (—SH) to the compound offormula (XV) or a salt or an activated ester derivative thereof:

-   X is O, S or NH;-   Y is O, S or NH;-   B is H or —CH₂R⁹;-   L is —C(═O), —C(═S), —C(═NH) or —S(O)₂;-   R⁷ is —N(R_(b))C(O)OR_(a), alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, heterocycle, aryl or heteroaryl; wherein the alkyl,    alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl and    heteroaryl are independently substituted with 0, 1 or 2 substituents    independently selected from the group consisting of halo, —OR_(a),    —OC(O)R_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —NR_(a)R_(b),    —N(R_(b))C(O)R_(a), —N(R_(b))C(O)OR_(a), —N(R_(a))C(═N)NR_(a)R_(b),    —N(R_(a))C(O)NR_(a)R_(b), —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(7a);-   R^(7a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(7a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R⁹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R⁹ is substituted with 0, 1,    2 or 3 substituents independently selected from the group consisting    of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro, oxo,    —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), SO₂NR_(a), —SO₂OR_(a),    NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))SO₂R_(a),    —N(R_(b))SO₂NR_(a)R_(b), —N(R_(b))C(O)NR_(a)R_(b),    —N(R_(b))C(O)OR_(a), —C(O)R_(a), —C(O)NR_(a)R_(b), —C(O)OR_(a),    haloalkyl, nitroalkyl, cynaoalkyl, formylalkyl, -alkylOR_(a),    -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)OR_(a), -alkylN(R_(b))SO₂NR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkylC(O)R_(a),    -alkylC(O)NR_(a)R_(b) and R^(9a);-   R^(9a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;    wherein each R^(9a) is substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of cyano, halo,    nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,    —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹⁰ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R¹⁰ is substituted with 0,    1, 2 or 3 substituents independently selected from the group    consisting of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro,    oxo, —OR, —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))SO₂R_(a),    —N(R_(b))SO₂NR_(a)R_(b), —N(R_(b))C(O)NR_(a)R_(b),    —N(R_(b))C(O)OR_(a), —C(O)R_(a), —C(O)NR_(a)R_(b), —C(O)OR_(a),    haloalkyl, nitroalkyl, cynaoalkyl, formylalkyl, -alkylOR_(a),    -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)OR_(a), -alkylN(R_(b))SO₂NR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkylC(O)R_(a),    -alkylC(O)NR_(a)R_(b) and R^(10a);-   R^(10a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or    heteroaryl; wherein each R^(10a) is substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R¹¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R¹¹ is substituted with 0,    1, 2 or 3 substituents independently selected from the group    consisting of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro,    oxo, —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))SO₂R_(a),    —N(R_(b))SO₂NR_(a)R_(b), —N(R_(b))C(O)NR_(a)R_(b),    —N(R_(b))C(O)OR_(a), —C(O)R_(a), —C(O)NR_(a)R_(b), —C(O)OR_(a),    haloalkyl, nitroalkyl, cynaoalkyl, formylalkyl, -alkylOR_(a),    -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)OR_(a), -alkylN(R_(b))SO₂NR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkylC(O)R_(a),    -alkylC(O)NR_(a)R_(b) and R^(11a);-   R^(11a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or    heteroaryl; wherein each R^(11a) is substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R¹² is alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl or    cycloalkenylalkyl; wherein each R¹² is substituted with 0, 1 or 2    substituents independently selected from the group consisting of    hydroxy, alkoxy and halo;-   R¹³ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,    heteroaryl or heterocycle; wherein each R¹³ is substituted with 0,    1, 2 or 3 substituents independently selected from the group    consisting of alkyl, alkenyl, alkynyl, cyano, halo, nitro, oxo,    —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a), —SO₂OR_(a),    —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))C(O)OR_(a),    —C(O)NR_(a)R_(b), —C(O)OR_(a), haloalkyl, nitroalkyl, cynaoalkyl,    -alkylOR_(a), -alkyl-O—P(O)(OR_(a))(OR_(a)), -alkylNR_(a)R_(b),    -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)NR_(a)R_(b),    -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a), -alkyl-C(O)NR_(a)R_(b) and    R^(13a);-   R^(13a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or    heteroaryl; wherein each R^(13a) is substituted with 0, 1, 2, 3 or 4    substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, haloalkyl,    hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),    -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂;-   R_(a) and R_(b) at each occurrence are independently selected from    the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    cycloalkyl, aryl, heteroaryl and heterocycle; wherein each R_(a) and    R_(b), at each occurrence, is independently substituted with 0, 1, 2    or 3 substituents independently selected from the group consisting    of cyano, nitro, halo, oxo, alkyl, alkenyl, alkynyl, hydroxy,    alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and R_(c);-   alternatively, R_(a) and R_(b), together with the nitrogen atom to    which they are attached, form a ring selected from the group    consisting of heteroaryl and heterocycle; wherein each of the    heteroaryl and heterocycle is independently substituted with 0, 1, 2    or 3 substituents independently selected from the group consisting    of alkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo,    hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),    —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl, formylalkyl,    nitroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH₂,    -alkylN(H)(alkyl), -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂,    -alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH,    -alkylC(O)Oalkyl, -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl),    -alkylC(O)N(alkyl)₂ and R_(c);-   R_(c) is aryl, heteroaryl or heterocycle; wherein each R_(c) is    independently substituted with 0, 1, 2, 3 or 4 substituents    independently selected from the group consisting of halo, nitro,    oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),    —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,    —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),    —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂,    —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkyl-NH₂, -alkyl-N(H)(alkyl), -alkyl-N(alkyl)₂,    -alkyl-N(H)C(O)NH₂, -alkyl-N(H)C(O)N(H)(alkyl),    -alkyl-N(H)C(O)N(alkyl)₂, -alkyl-C(O)OH, -alkyl-C(O)Oalkyl,    -alkyl-C(O)NH₂, -alkyl-C(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂; and-   n is 1 or 2.

The present invention is also related to the process of preparing acompound of formula (XVIII)

wherein

-   X₁ is CH or N;-   X₂ is CH or N;-   X₃ is CH or N; provided only one of X₁, X₂, X₃ is N and the other    two are CH;-   R¹¹² is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl    heterocycle, aryl or heteroaryl; wherein each R¹¹² is substituted    with 0, 1 or 2 substituents independently selected from the group    consisting of halo, —OR_(a), —SR_(a′), —SO_(a′), —SO₂R_(a′),    —NR_(a′)R_(b′), —N(R_(b′))C(O)R_(a′), —N(R_(b′))C(O)OR_(a′),    —N(R_(b′))C(═N)NR_(a′)R_(b′), —N(R_(b′))C(O)NR_(a′)R_(b′),    —C(O)NR_(a′)R_(b′), —C(O)OR_(a′), and R^(112a);-   R^(112a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or    heteroaryl; wherein each R^(112a) is substituted with 0, 1, 2, 3 or    4 substituents independently selected from the group consisting of    cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy,    —NH₂, —N(H)(alkyl), -N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),    —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,    —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,    —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,    alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,    -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),    -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl,    -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂;-   R¹¹¹ is C₁-C₆ alkyl or phenylmethyl; and-   R_(a′) and R_(b′) are each independently selected from the group    consisting of hydrogen and alkyl.    wherein the process comprises the steps of:    -   (a) contacting a compound of formula (i)

with potassium tert-butoxide and n-butyl lithium in a first solvent;

-   -   (b) contacting a first base with ketonitrile of formula (ii)

wherein P₁ and P₂ are nitrogen protecting group and P₁ and P₂ can be thesame or different, in the first solvent;

-   -   (c) contacting the product of step (b) with the product of        step (a) to provide a compound of formula (iii)

-   -   (d) contacting the compound of formula (iii) with a first        reducing agent and an acid in a second solvent;    -   (e) contacting the product of step (d) in the second solvent        with a second reducing agent, to provide a compound of formula        (iv);

-   -   (f) contacting the compound of formula (iv) with a hydrogen        source and a catalyst in a third solvent to provide a compound        of formula (v);

and

-   -   (g) contacting the compound of formula (v) with a compound of        formula (vi),

a coupling reagent and a second base in a fourth solvent to provide thecompound of formula (XVIII).

In step (a), about one to about 1.6 molar equivalent of potassiumtert-butoxide is first 20 mixed with about one equivalent of thecompound of formula (i) in a first solvent for a period of about 5minutes to about 30 minutes, followed by the addition of about one toabout 1.6 molar equivalents of n-butyl lithium. Alternatively potassiumtert-butoxide and n-butyl lithium can be premixed in the first solvent,followed by the addition of the compound of formula (i). The temperatureat which the mixings can be carried out is from about −78° C. to about0° C., preferably at a temperature from about −25° C. to about 0° C. andmost preferably at a temperature from about −20° C. to about −10° C.After complete mixing of all three reagents, the reaction mixture can bestirred at a temperature from about room temperature to about 35° C.,preferably at about room temperature, for a period of about 30 minutesto about 3 hours, preferably for about 1 hour.

The first solvent used in step (a) refers to any organic solvent thatwill allow the reaction in step (a) to proceed to completion orsubstantially to completion. Examples of the first solvent include, butare not limited to, tetrahydrofuran, tert-butyl methyl ether anddimethyl ether preferably tetrahydrofuran.

About one equivalent of ketonitrile of formula (ii) in the first solventis pre-cooled to a temperature of about −10° C. to about 10° C.,preferably at about −5° C. to about 5° C., followed by addition of afirst base at a temperature from about −10° C. to about 10° C.,preferably at about −5° C. to about 5° C. The mixture is then stirred ata temperature from about −10° C. to about 10° C., preferably at about−5° C. to about 5° C., for a period from about 15 minutes to about 1hour, preferably for about 30 minutes.

Examples of the first base in step (a) include, but are not limited totert-butyl magnesium chloride and tert-butyl magnesium bromide,preferably tert-butyl magnesium chloride.

The product of step (b) is treated with the product of step (a) at atemperature from about −10° C. to about 10° C., preferably at about −5°C. to about 5° C. and the reaction mixture is stirred a temperature fromabout 10° C. to about 25° C., preferably at about 25° C., for about 1hour to about 24 hours, preferably for about 20 hours. The product ofstep (c) is isolated by first quenching the reaction mixture withsaturated ammonium chloride solution, diluting the solution with ethylacetate, stirring the solution, separating the aqueous phase from theorganic phase; wash the organic phase sequentially with ammoniumchloride; drying the organic phase over sodium sulfate; andconcentrating the organic phase to provide the compound of formula(iii).

The compound of formula (iii) in a second solvent is cooled to atemperature from about −20° C. to about 10° C., preferably at atemperature from about −15° C. to about 0° C., and most preferably atabout −15° C., followed by addition of an acid. The mixture is cooled toa temperature from about −20° C. to about 10° C., preferably at atemperature from about −15° C. to about 0° C., and most preferably atabout −15° C., followed by the addition of about 5 molar equivalents ofa first reducing agent. The mixture is stirred for a period from about 1hour to about 24 hours, preferably for about 3 hours, at a temperaturefrom about −20° C. to about 10° C., preferably at a temperature fromabout −15° C. to about 0° C., and most preferably at about −15° C.

The second solvent is a mixture of solvents selected from an alcohol(for example isopropyl alcohol, ethanol, methanol, and the like) and anamide (for example, N,N-dimethylformamide, dimethylacetamide, and thelike). Preferred second solvent is a mixture of dimethylacetamide andisopropyl alcohol in a ratio of about 10:1 (volume:volume).

Examples of the acid used in step (d) include, but are not limited to,methane sulfonic acid, acetic acid, and sulfuric acid. Preferred acidfor step (d) is methane sulfonic acid.

Examples of the first reducing agent include, but are not limited to,sodium triacetoxyborohydride, sodium borohydride. Preferred firstreducing agent is sodium triacetoxyborohydride.

The reaction in step (d) is quenched with the addition of about 10 toabout 15 molar equivalents of an organic amine. The reaction mixture isstirred at a temperature from about −20° C. to about 0° C., preferablyat about −15° C., for a period of about 15 minutes to about 2 hours,preferably for about 1 hour. Examples of the organic amine include, butare not limited to, triethylamine, triethanolamine, and diisopropylethylamine. A preferred organic amine is triethanolamine.

The product of step (d) can be reacted with a second reducing agent,either in situ or after isolation. Preferred procedure is to mix thesecond reducing agent with the product of step (d) in the secondsolvent, after quenching with the organic amine, without isolation ofthe product of step (d).

Examples of the second reducing agent used in step (e) include, but arenot limited to, sodium borohydride and lithium borohydride. Preferredsecond reducing agent is sodium borohydride.

The reduction reaction between the second reducing agent and the productof step (d) is conducted at a temperature from about −20° C. to aboutroom temperature, preferably at a temperature from about −15° C. toabout 0 C, most preferably at a temperature from about −15° C. to about−10° C., for a period from about 1 hour to about 30 hours, preferablyfor a period from about 10 to about 24 hours.

The product from step (e) is isolated by quenching the reaction mixturewith water, extracting with isopropyl acetate, separating the organicphase from aqueous phase, extracting the isolated isopropyl acetate withdilute H₃PO₄ solution (preferably at a concentration of about 0.35 toabout 1%, most preferably 0.3%), adjusting the pH of the isolatedaqueous layer to about 6-7 with a base such as sodium carbonate,extracting with isopropyl acetate, washing the isolated organic phasewith 5% aqueous KH₂PO₄, drying over a drying agent such as sodiumsulfate or magnesium sulfate, filtering and concentrating to providecompounds of formula (iv).

P₁ and P₂ in compounds of formula (iv) are nitrogen protecting groupsand can be the same or different. Examples of nitrogen protecting groupsthat can be employed in this process include, but are not limited to,9-fluorenylmethyl oxycarbonyl, tert-butyloxycarbonyl, benzyloxycarbonyl, p-methoxybenzyl oxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl and benzyl. Preferred nitrogen protecting group aretert-butyloxycarbonyl, benzyl oxycarbonyl and benzyl. Most preferrednitrogen protecting group is benzyl.

Compounds of formula (iv) can be converted to compounds of formula (v)by reacting with a deprotecting reagent. Examples of the deprotectingagent are well known in the art and are illustrated in Protective Groupsin Organic Synthesis, 3^(rd) edition, T. W. Greene, P. G. M. Wuts, JohnWiley & Sons, Inc., 1998. In the case wherein both P₁ and P₂ are benzyl,compounds of formula (iv) can be converted to compounds of formula (v)by reacting with a hydrogen source and a catalyst in a third solvent.

Examples of the third solvent include, but are not limited to, ethylacetate, isopropyl alcohol, methanol, ethanol tetrahydrofuran, anddioxane. A preferred third solvent is methanol.

Examples of the hydrogen source include, but are not limited to,hydrogen gas, ammonium formate, and formic acid. Preferred hydrogensource is ammonium formate.

Examples of the catalyst include, but are not limited to, palladium oncarbon, palladium hydroxide on carbon, and platinum oxide. Preferredcatalyst is palladium on carbon.

The reaction is generally conducted at a temperature from about roomtemperature to about 80° C., preferably at a temperature from about 35°C. to about 70° C., most preferably at a temperature from about 50° C.to about 65° C., for a period from about 1 hour to about 20 hours,preferably for a period from about 8 to about 15 hours, under an inertatmosphere (e.g. nitrogen or argon gas).

The product of step (f) is isolated by filtering the reaction mixture,concentrating the filtrate, diluting the concentrate in dichloromethane,washing with aqueous sodium bicarbonate, separating the aqueous phasefrom the organic phase, drying the organic phase over sodium sulfate,filtering and concentrating the organic phase.

Compounds of formula (XVIII) can be obtained from compounds of formula(v) by reacting with compounds of formula (vi), a coupling reagent and asecond base in a fourth solvent.

Examples of the coupling reagent include, but are not limited to,O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TBTU), bis(2-oxo-3-oxazolidinyl)phosphinic chloride(BOPCl), benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (BOP), 1-hydroxybenzotriazole hydrate (HOBT),3-hydroxy-1,2,3-benzotriazin-4(3H)-one (HOOBT) and1,3-di-tert-butylcarbodiimide. Preferred coupling reagent for step (g)is O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU).

Examples of the second base include, but are not limited to,triethylamine, diisopropylethylamine, sodium carbonate, potassiumcarbonate. Preferred second base for the reaction isdiisopropylethylamine.

Examples of the fourth solvent include acetonitrile, ethyl acetate,dichloromethane, tetrahydrofuran, dioxane, and mixtures thereof.Preferred fourth solvent is a mixture of ethyl acetate and acetonitrilein a ratio of about 10:1 (volume:volume).

A mixture of compound of formula (vi), coupling reagent, and the secondbase in a molar ratio of about 2:2:6 in the fourth solvent is stirred atabout room temperature for a period of about 30 minutes to about 3hours, followed by addition of about 1 equivalent of the compound offormula (v) in ethyl acetate. The reaction mixture is stirred for aperiod from about 8 hours to about 24 hours, preferably 24 hours, at atemperature from about room temperature to about 50° C., preferably atabout room temperature. The product is isolated by filtering, dissolvingthe isolated solid in acetonitrile at a temperature from about 70° C. toabout 80° C., cooling the solution to about room temperature, stirringthe cooled solution for a period of about 30 minutes to about 2 hours,filtering, washing the isolated solid with acetonitrile and drying thesolid.

The term “nitrogen protecting group”, “N-protecting group” or“N-protected” as used herein refers to those groups intended to protectthe N-terminus of an amino acid or peptide or to protect an amino groupagainst undesirable reactions during synthetic procedures. Commonly usedN-protecting groups are disclosed in T. H. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 2nd edition, John Wiley & Sons,New York (1991). N protecting groups comprise acyl groups such asformyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chlorcacetyl,2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl,o-nitrophenoxyacetyl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl,4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl,p-toluenesulfonyl and the like; sulfenyl groups such as phenylsulfenyl(phenyl-S—), triphenylmethylsulfenyl (trityl-S—) and the like; sulfinylgroups such as p-methylphenylsulfinyl (p-methylphenyl-S(O)—),t-butylsulfinyl (t-Bu-S(O)—) and the like; carbamate forming groups suchas benzyloxycarbonyl, p-chlorobezzyloxycarbonyl,p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1-(biphenylyl)-1-methylethoxycarbonyl,dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl,t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl,ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl,2,2,2-trichloro-ethoxy-carbonyl, phenoxycarbonyl,4-nitro-phenoxycarbonyl, fluorenyl-9-methoxycarbonyl,cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl,phenylthiocarbonyl and the like; alkyl groups such as benzyl,p-methoxybenzyl, triphenylmethyl, benzyloxymethyl and the like;p-methoxyphenyl and the like; and silyl groups such as trimethylsilyland the like. Preferred N-protecting groups include formyl, acetyl,benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl,t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

As used herein, the terms “S” and “R” configuration are as defined bythe IUPAC 1974 Recommendations for Section E, FundamentalStereochemistry, Pure Appl. Chem. (1976) 45, 13-30.

The compounds of the invention can comprise asymmetrically substitutedcarbon atoms. As a result, all stereoisomers of the compounds of theinvention are meant to be included in the invention, including racemicmixtures, mixtures of diastereomers, as well as individual opticalisomers, including, enantiomers and single diastereomers of thecompounds of the invention substantially free from their enantiomers orother diastereomers. By “substantially free” is meant greater than about80% free of other enantiomers or diastereomers of the compound, morepreferably greater than about 90% free of other enantiomers ordiastereomers of the compound, even more preferably greater than about95% free of other enantiomers or diastereomers of the compound, evenmore highly preferably greater than about 98% free of other enantiomersor diastereomers of the compound and most preferably greater than about99% free of other enantiomers or diastereomers of the compound.

In addition, compounds comprising the possible geometric isomers ofcarbon-carbon double bonds and carbon-nitrogen double are also meant tobe included in this invention.

Individual stereoisomers of the compounds of this invention can beprepared by any one of a number of methods which are within theknowledge of one of ordinary skill in the art. These methods includestereospecific synthesis, chromatographic separation of diastereomers,chromatographic resolution of enantiomers, conversion of enantiomers inan enantiomeric mixture to diastereomers and then chromatographicallyseparating the diastereomers and regeneration of the individualenantiomers, enzymatic resolution and the like.

Stereospecific synthesis involves the use of appropriate chiral startingmaterials and synthetic reactions which do not cause racemization orinversion of stereochemistry at the chiral centers.

Diastereomeric mixtures of compounds resulting from a synthetic reactioncan often be separated by chromatographic techniques which arewell-known to those of ordinary skill in the art.

Chromatographic resolution of enantiomers can be accomplished on chiralchromatography resins. Chromatography columns containing chiral resinsare commercially available. In practice, the racemate is placed insolution and loaded onto the column containing the chiral stationaryphase. The enantiomers are then separated by HPLC.

Resolution of enantiomers can also be accomplished by converting theenantiomers in the mixture to diastereomers by reaction with chiralauxiliaries. The resulting diastereomers can then be separated by columnchromatography. This technique is especially useful when the compoundsto be separated contain a carboxyl, amino or hydroxyl group that willform a salt or covalent bond with the chiral auxiliary. Chirally pureamino acids, organic carboxylic acids or organosulfonic acids areespecially useful as chiral auxiliaries. Once the diastereomers havebeen separated by chromatography, the individual enantiomers can beregenerated. Frequently, the chiral auxiliary can be recovered and usedagain.

Enzymes, such as esterases, phosphatases and lipases, can be useful forresolution of derivatives of the enantiomers in an enantiomeric mixture.For example, an ester derivative of a carboxyl group in the compounds tobe separated can be prepared. Certain enzymes will selectively hydrolyzeonly one of the enantiomers in the mixture. Then the resultingenantiomerically pure acid can be separated from the unhydrolyzed ester.

In addition, esters, amides, solvates and hydrates of the compounds offormula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X),(XI), (XII) or (XIII) are meant to be included in this invention.

When any variable (for example X, R₁₀₃, R₁₀₄, R₁₀₅, R₁₀₆, R₁₀₇, R₁₀₈,R_(a), R_(b), R_(c), M, Q, etc.) occurs more than one time in anysubstituent or in the compound of formula (I), (II), (III), (IV), (V),(VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI),(XVII) or any other formula herein, its definition on each occurrence isindependent of its definition at every other occurrence. In addition,combinations of substituents are permissible only if such combinationsresult in stable compounds. Stable compounds are compounds which can beisolated in a useful degree of purity from a reaction mixture.

The compounds of the present invention can be used in the form of saltsderived from inorganic or organic acids. These salts include but are notlimited to the following: 4-acetamidobenzoate, acetate, adipate,alginate, carbonate, 4-chlorobenzenesulfonate, citrate, aspartate,benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, cholate, digluconate, cyclopentanepropionate,dichloroacetate, dodecylsulfate, ethanedisulfonate, ethanesulfonate,ethylsuccinate, formate, fumarate, galactarate, D-gluconate,D-glucuronate, glucoheptanoate, glutarate, lycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate (isethionate),3-hydroxy-2-naphthoate, 1-hydroxy-2-naphthoate, lactate, lactobionate,laurate, maleate, malonate, mandelate, methanesulfonate, nicotinate,1,5-naphthalene-disulfonate, 2-naphthalenesulfonate, oleate, oxalate,pamoate, palmitate, pectinate, persulfate, 3-phenylpropionate, picrate,pivalate, propionate, L-pyroglutamate, sebacate, stearate, succinate,tartrate, terephthalate, thiocyanate, p-toluenesulfonate, undecanoate,undecylenoate and valerate. Also, the basic nitrogen-containing groupscan be quaternized with such agents as lower alkyl halides, such asmethyl, ethyl, propyl, and butyl chloride, bromides, and iodides;dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates,long chain halides such as decyl, lauryl, myristyl and stearylchlorides, bromides and iodides, aralkyl halides like benzyl andphenethyl bromides, and others. Water or oil-soluble or dispersibleproducts are thereby obtained.

Examples of acids which may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulphuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, succinic acid and citric acid. Othersalts include salts with alkali metals or alkaline earth metals, such asaluminum, sodium, lithium, potassium, calcium, magnesium or zinc or withorganic bases such as diethylethanolamine, diethanolamine,ethylenediamine, guanidine, meglumine, olamine (ethnolamine),piperazine, piperidine, triethylamine, tromethamine, benzathine,benzene-ethanamine, adenine, cytosine, diethylamine, glucosamine,guanine, nicotinamide, hydrabamine, tributylamine, deanol, epolamine ortriethanolamine.

Representative salts of the compounds of the present invention include,but not limited to, hydrochloride, bis hydrochloride, mosodium,disodium, methanesulfonate, sulfonate, phosphonate, isethionate andtrifluoroacetate.

The compounds of the present invention can also be used in the form ofprodrugs. Examples of such prodrugs include compounds wherein one, twoor three hydroxy groups in the compound of this invention arefunctionalized with R¹⁵ wherein R¹⁵ is

-   R₁₀₃ is C(R₁₀₅)₂, O or —N(R₁₀₅);-   R₁₀₄ is hydrogen, alkyl, haloalkyl, alkoxycarbonyl, aminocarbonyl,    alkylaminocarbonyl or dialkylaminocarbonyl,-   each M is independently selected from the group consisting of H,    —N(R₁₀₅)₂, alkyl, alkenyl, and R₁₀₆; wherein 1 to 4 —CH₂ radicals of    the alkyl or alkenyl, other than the —CH₂ radical that is bound to    Z, is optionally replaced by a heteroatom group selected from the    group consisting of O, S, S(O), SO₂ and N(R₁₀₅); and wherein any    hydrogen in said alkyl, alkenyl or R₁₀₆ is optionally replaced with    a substituent selected from the group consisting of oxo, —OR₁₀₅,    —R₁₀₅, —N(R₁₀₅)₂, —CN, —C(O)OR₁₀₅, —C(O)N(R₁₀₅)₂, —SO₂N(R₁₀₅),    —N(R₁₀₅)C(O)R₁₀₅, —C(O)R₁₀₅, —SR₁₀₅, —S(O)R₁₀₅, —SO₂R₁₀₅, —OCF₃,    —SR₁₀₆, —SOR₁₀₆, —SO₂R₁₀₆, —N(R₁₀₅)SO₂R₁₀₅, halo, —CF₃, NO₂ and    phenyl; provided that when M is —N(R₁₀₅)₂, Z₁ and Z₂ are —CH₂;-   Z₁ is CH₂, O, S, —N(R₁₀₅), or, when M is absent H;-   Z₂ is CH₂, O, S or —N(R₁₀₅);-   Q is O or S;-   W is P or S; wherein when W is S, Z₁ and Z₂ are not S;-   M′ is H, alkyl, alkenyl or R₁₀₆; wherein 1 to 4 H₂ radicals of the    alkyl or alkenyl is optionally replaced by a heteroatom group    selected from O, S, S(O), SO, or N(R₁₀₅); and wherein any hydrogen    in said alkyl, alkenyl or R₁₀₆ is optionally replaced with a    substituent selected from the group consisting of oxo, —OR₁₀₅,    —R₁₀₅, —N(R₁₀₅)₂, —CN, —C(O)OR₁₀₅, —C(O)N(R₁₀₅)₂, —SO₂N(R₁₀₅),    —N(R₁₀₅)C(O)R₁₀₅, —C(O)R₁₀₅, —SR₁₀₅, —S(O)R₁₀₅, —SO₂R₁₀₅, —OCF₃,    —SR₁₀₆, —SOR₁₀₆, —SO₂R₁₀₆, —N(R₁₀₅)SO₂R₁₀₅, halo, —CF₃ and NO₂;-   R₁₀₆ is a monocyclic or bicyclic ring system selected from the group    consisting of aryl, cycloalkyl, cycloalkenyl heteroaryl and    heterocycle; wherein any of said heteroaryl and heterocycle ring    systems contains one or more heteroatoms selected from the group    consisting of O, N, S, SO, SO₂ and N(R₁₀₅); and wherein any of said    ring system is substituted with 0, 1, 2, 3, 4, 5 or 6 substituents    selected from the group consisting of hydroxy, alkyl, alkoxy, and    —OC(O)alkyl;-   each R₁₀₅ is independently selected from the group consisting of H    or alkyl; wherein said alkyl is optionally substituted with a ring    system selected from the group consisting of aryl, cycloalkyl,    cycloalkenyl, heteroaryl and heterocycle; wherein any of said    heteroaryl and heterocycle ring systems contains one or more    heteroatoms selected from the group consisting of O, N, S, SO, SO₂,    and N(R₁₀₅); and wherein any one of said ring systems is substituted    with 0, 1, 2, 3 or 4 substituents selected from the group consisting    of oxo, —OR₁₀₅, —R₁₀₅, —N(R₁₀₅)₂, —N(R₁₀₅)C(O)R₁₀₅, —CN, —C(O)OR₁₀₅,    —C(O)N(R₁₀₅)₂, halo and —CF₃;-   each R₁₀₇ and R₁₀₈ are independently selected from the group    consisting of hydrogen and alkyl;-   q is 0 or 1;-   m is 0 or 1;-   m′ is 0 or 1;-   m″ is 0 or 1;-   r is 0, 1, 2, 3 or 4; and-   t is 0 or 1.

It will be understood by those of skill in the art that component M orM′ in the formulae (XVI) and (XVII) set forth herein will have either acovalent, a covalent/zwitterionic, or an ionic association with eitherZ₁, Z₂ or R₁₀₃ depending upon the actual choice for M or M′. When M orM′ is hydrogen, alkyl, alkenyl or R₁₀₆, then M or M′, is covalentlybound to —R₁₀₃ Z₁, or Z₂. If M is a mono or bivalent metal or othercharged species (i.e. NH₄ ⁺), there is an ionic interaction between Mand Z₁ or Z₂ and the resulting compound is a salt.

These prodrugs of the compound of the present invention serve toincrease the solubility of these compounds in the gastrointestinaltract. These prodrugs also serve to increase solubility for intravenousadministration of the compound. These prodrugs may be prepared by usingconventional synthetic techniques. One of skill in the art would be wellaware of conventional synthetic reagents to convert one or more of thehydroxy groups of the compounds of the present invention to a desiredprodrug, functionalized by the substituents of formula (XVI) or (XVII)as defined above.

The prodrugs of this invention are metabolized in vivo to provide thecompound of this invention. Additionally, prodrugs can be converted tothe compounds of the present invention by chemical or biochemicalmethods in an ex vivo environment. For example, prodrugs can be slowlyconverted to the compounds of the present invention when placed in atransdermal patch reservoir with a suitable enzyme or chemical reagent.

The compounds of the invention are useful for inhibiting retroviralprotease, in particular HIV protease, in vitro or in vivo (especially inmammals and in particular in humans). The compounds of the presentinvention are also useful for the inhibition of retroviruses in vivo,especially human immunodeficiency virus (HIV). The compounds of thepresent invention are also useful for the treatment or prophylaxis ofdiseases caused by retroviruses, especially acquired immune deficiencysyndrome or an HIV infection in a human or other mammal.

Total daily dose administered to a human or other mammal host in singleor divided doses may be in amounts, for example, from 0.001 to 300 mg/kgbody weight daily and more usually 0.1 to 20 mg/kg body weight daily.Dosage unit compositions may contain such amounts of submultiplesthereof to make up the daily dose.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination, and the severity ofthe particular disease undergoing therapy.

The compounds of the present invention may be administered orally,parenterally, sublingually, by inhalation spray, rectally, or topicallyin dosage unit formulations containing conventional nontoxicpharmaceutically acceptable carriers, adjuvants, and vehicles asdesired. Topical administration may also involve the use of transdermaladministration such as transdermal patches or iontophoresis devices. Theterm parenteral as used herein includes subcutaneous injections,intravenous, intramuscular, intrasternal injection, or infusiontechniques.

Injectable preparations, for example, sterile injectable aqueous oroleagenous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-propanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono-ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable nonirritating excipient such as cocoabutter and polyethylene glycols which are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose lactose or starch. Such dosage forms may also comprise, as isnormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coating.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring, andperfuming agents.

The compounds of the present invention can also be administered in theform of liposomes. As is known in the art, liposomes are generallyderived from phospholipids or other lipid substances. Liposomes areformed by mono-or multi-lamellar hydrated liquid crystals that aredispersed in an aqueous medium. Any nontoxic, physiologically acceptableand metabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to thecompound of the present invention, stabilizers, preservatives,excipients, and the like. The preferred lipids are the phospholipids andphosphatidyl cholines (lecithins), both natureal and synthetic.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33.

While the compound of the invention can be administered as the soleactive pharmaceutical agent, it can also be used in combination with oneor more immunomodulators, antiviral agents, other antiinfective agentsor vaccines. Other antiviral agents to be administered in combinationwith a compound of the present invention include AL-721, betainterferon, polymannoacetate, reverse transcriptase inhibitors (forexample, BCH-189, AzdU, carbovir, ddA, d4C, d4T (stavudine), 3TC(lamivudine) DP-AZT, FLT (fluorothymidine), BCH1189,5-halo-3′-thia-dideoxycytidine, PMEA, bis-POMPMEA, zidovudine (AZT),MSA-300, trovirdine, R82193, L-697,661, BI-RG-587 (nevirapine),abacavir, zalcitabine, didanosine, tenofovir, emtricitabine, amdoxovir,elvucitabine, alovudine, MIV-210, Racivir (±-FTC), D-D4FC (Reverset,DPC-817), SPD754, nevirapine, delavirdine, efavirenz, capravirine,emivirine, calanolide A, GW5634, BMS-56190 (DPC-083), DPC-961, MIV-150,TMC-120, and TMC-125 and the like), retroviral protease inhibitors (forexample, HIV protease inhibitors such as ritonavir, lopinavir,saquinavir, amprenavir (VX-478), fosamprenavir, nelfmavir (AG1343),tipranavir, indinavir, atazanavir, TMC-126, TMC-114, mozenavir(DMP-450), JE-2147 (AG1776), L-756423, R00334649, KNI-272, DPC-681,DPC-684, GW640385X, SC-52151, BMS 186,318, SC-55389a, BELA 1096 BS,DMP-323, KNI-227, and the like), HEPT compounds, L,697,639, R82150,U87201E and the like), HIV integrase inhibitors (S-1360, zintevir(AR-177), L-870812 L-870810 and the like), TAT inhibitors (for example,RO-247429 and the like), trisodium phosphonoformate, HPA-23,eflonithine, Peptide T, Reticulose (nucleophosphoprotein), ansamycin LM427, trimetrexate, UA001, ribavirin, alpha interferon, oxetanocin,oxetanocin-G, cylobut-G, cyclobut-A, ara-M, BW882C87, foscarnet,BW256U87, BW348U87, L-693,989, BV ara-U, CMV triclonal antibodies, FIAC,HOE-602, HPMPC, MSL-109, TI-23, trifluridine, vidarabine, famciclovir,penciclovir, acyclovir, ganciclor, castanosperminem rCD4/CD4-IgG,CD4-PE40, butyl-DNJ, hypericin, oxamyristic acid, dextran sulfate andpentosan polysulfate. Other agents that can be administered incombination with the compound of the present invention include HIVentry/fusion inhibitor (for example, enfuivirtide (T-20), T-1249, PRO2000, PRO 542, PRO 140, AMD-3100, BMS-806, FP21399, GW873140, Schering C(SCH-C), Schering D (SCH-D), TNX-355, UK-427857, and the like) and HIVbudding/maturation inhibitor such as PA-457. Immunomodulators that canbe administered in combination with the compound of the presentinvention include bropiriiine, Ampligen, anti-human alpha interferonantibody, colony stimulting factor, CL246,738, Imreg-1, Imreg-2,diethydithiocarbamate, interleukin-2, alpha-interferon, inosinepranobex, methionine enkephalin, muramyl-tripeptide, TP-5,erythropoietin, naltrexone, tumor necrosis factor, beta interferon,gamma interferon, interleukin-3, interleukin-4, autologous CD8+infusion, alpha interferon immunoglobulin, IGF-1, anti-Leu3A,autovaccination, biostimulation, extracorporeal photophoresis,cyclosporin, rapamycin, FK-565, FK-506, GCSF, GM-CSF, hyperthermia,isopinosine, IVIG, HIVIG, passive immunotherapy and polio vaccinehyperimmunization. Other antiinfective agents that can be administeredin combination with the compound of the present invention includepentamidine isethionate. Any of a variety of HIV or AIDS vaccines (forexample, gp120 (recombinant), Env 2-3 (gp120), HIVAC-1e (gp120), gp160(recombinant), VaxSyn HIV-1 (gp160), Immuno-Ag (gp160), HGP-30,HIV-Immunogen, p24 (recombinant), VaxSyn HIV-1 (p24)) can be used incombination with the compound of the present invention.

Other agents that can be used in combination with the compound of thisinvention are ansamycin LM 427, apurinic acid, ABPP, Al-721, carrisyn,AS-101, avarol, azimexon, colchicine, compound Q, CS-85, N-acetylcysteine, (2-oxothiazolidine-4-carboxylate), D-penicillamine,diphenylhydantoin, EL-10, erythropoieten, fusidic acid, glucan, HPA-23,human growth hormone, hydroxchloroquine, iscador, L-ofloxacin or otherquinolone antibiotics, lentinan, lithium carbonate, MM-1, monolaurin,MTP-PE, naltrexone, neurotropin, ozone, PAI, panax ginseng,pentofylline, pentoxifylline, Peptide T, pine cone extract,polymannoacetate, reticulose, retrogen, ribavirin, ribozymes, RS-47,Sdc-28, silicotungstate, THA, thymic humoral factor, thymopentin,thymosin fraction 5, thymosin alpha one, thymostimulin, UA001, uridine,vitamin B12 and wobemugos.

Other agents that can be used in combination with the compound of thisinvention are antifungals such as amphotericin B, clotrimazole,flucytosine, fluconazole, itraconazole, ketoconazole and nystatin andthe like.

Other agents that can be used in combination with the compound of thisinvention are antibacterials such as amikacin sulfate, azithromycin,ciprofloxacin, tosufloxacin, clarithromycin, clofazirnine, ethambutol,isoniazid, pyrazinamide, rifabutin, rifampin, streptomycin and TLC G-65and the like.

Other agents that can be used in combination with the compound of thisinvention are anti-neoplastics such as alpha interferon, COMP(cyclophosphamide, vincristine, methotrexate and prednisone), etoposide,mBACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide,vincristine and dexamethasone), PRO-MACE/MOPP (prednisone, methotrexate(w/leucovin rescue), doxorubicin, cyclophosphamide, taxol,etoposide/mechlorethamine, vincristine, prednisone and procarbazine),vincristine, vinblastine, angioinhibins, pentosan polysulfate, plateletfactor 4 and SP-PG and the like.

Other agents that can be used in combination with the compound of thisinvention are drugs for treating neurological disease such as peptide T,ritalin, lithium, elavil, phenytoin, carbamazipine, mexitetine, heparinand cytosine arabinoside and the like.

Other agents that can be used in combination with the compound of thisinvention are anti-protozoals such as albendazole, azithromycin,clarithromycin, clindamycin, corticosteroids, dapsone, DIMP,eflornithine, 566C80, fansidar, furazolidone, L,671,329, letrazuril,metronidazole, paromycin, pefloxacin, pentamidine, piritrexim,primaquine, pyrimethamine, somatostatin, spiramycin, sulfadiazine,trimethoprim, TMP/SMX, trimetrexate and WR 6026 and the like.

For example, a compound or combination of compounds of this invention,or a pharmaceutically acceptable salt form, prodrug or stereoisomerthereof can be administered in combination with ritonavir or itspharmaceutically acceptable salt form or prodrug thereof. Such acombination is especially useful for inhibiting HIV protease in a human.Such a combination is also especially useful for inhibiting or treatingan HIV infection in a human. When used in such a combination thecompound of this invention (or a pharmaceutically acceptable salt formor prodrug thereof) and ritonavir (or a pharmaceutically acceptable saltform or prodrug thereof) can be administered as separate agents at thesame or different times or they can be formulated as a singlepharmaceutical composition comprising both active ingredients, or asseparate pharmaceutical compositions each comprising an activeingredient and the pharmaceutical compositions can be administered atthe same or different time.

When administered in combination with a compound, or combination ofcompounds of this invention (or a pharmaceutically acceptable salt formor prodrug thereof), ritonavir (or a pharmaceutically acceptable saltform or prodrug thereof) causes an improvement in the pharmacokinetics(i.e., increases half-life, increases the time to peak plasmaconcentration, increases blood levels) of the compound of thisinvention.

Another combination can comprise of a compound, or combination ofcompounds of the present invention with ritonavir and one or morereverse transcriptase inhibitors (for example, lamivudine, stavudine,zidovudine, abacavir, zalcitabine, didanosine, tenofovir, emtricitabine,amdoxovir, elvucitabine, alovudine, MIV-210, Racivir (±-FTC), D-D4FC(Reverset, DPC-817), SPD754, nevirapine, delavirdine, efavirenz,capravirine, emivirine, calanolide A, GW5634, BMS-56190 (DPC-083),DPC-961, MIV-150 TMC-120, TMC-125 and the like). Yet another combinationcan comprise of a compound, or combination of compounds of the presentinvention with ritonavir and one or more HIV entry/fusion inhibitors.Such combinations are useful for inhibiting or treating an HIV infectionin a human. When used in such a combination the compound or combinationof compounds of the present invention and ritonavir and one or morereverse transcriptase inhibitors or HIV entry/fusion inhibitors can beadministered as separate agents at the same or different times or theycan be formulated as a single pharmaceutical composition comprising twoor more of the compounds, or formulated as separate pharmaceuticalcompositions each comprising one or more of the active ingredients andthat the pharmaceutical compositions can be administered at the same ordifferent time.

It will be understood that agents which can be combined with thecompound of the present invention for the inhibition, treatment orprophylaxis of AIDS or an HIV infection are not limited to those listedabove, but include in principle any agents useful for the treatment orprophylaxis of AIDS or an HIV infection.

When administered as a combination, the therapeutic agents can beformulated as separate compositions which are given at the same time ordifferent times, or the therapeutic agents can be given as a singlecomposition.

Antiviral Activity

Determination of Activity Against Wild-type HIV or the Passaged Variants

MT4 cells were infected with 0.003 multiplicity of infection (MOI) ofwild-type HIV-1 or the passaged mutant variants at 1×10⁶ cells/mL for 1h, washed twice to remove unabsorbed virus and resuspended to 1×10⁵cells/mL of medium, seeded in a 96-well plate at 100 μL/well, andtreated with an equal volume of solution of inhibitor in a series ofhalf log dilutions in RPMI 1640 (Rosewell Park Memorial Institute) media(Gibco) containing 10% fetal bovine serum (FBS), in triplicate. Thefinal concentration of DMSO in all wells was 0.5%. The virus controlculture was treated in an identical manner except no inhibitor was addedto the medium. The cell control was incubated in the absence ofinhibitor or virus. Plates were incubated for 5 days in a CO₂ incubatorat 37° C. On day 5, stock solution of3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) (4mg/mL in PBS, Sigma cat. #M 5655) was added to each well at 25 μL perwell. Plates were further incubated for 4 hrs, then treated with 20%sodium dodecyl sulfate (SDS) plus 0.02 N HCl at 50 μL per well to lysethe cells. After an overnight incubation, optical density (O.D.) wasmeasured by reading the plates at 570/650 nm wavelengths on a Bio-Tekmicrotitre plate reader. Percent cytopathic effect (CPE) reduction wascalculated from the formula below:((O.D. test well−O.D. infected control well)/(O.D. uninfected controlwell−O.D. infected control well))×100

EC₅₀ values were determined from the plot of log (Fa/Fu) vs. log(compound concentration) using the median-effect equation (Chou, 1975,Proc. Int. Cong. Pharmacol. 6^(th)p. 619) wherein Fa is the fractioninhibited by the compound, and Fu is the fraction uninhibited (1−Fa).

When tested by the above method, the compounds of the present inventionexhibit EC₅₀ in the range of 0.7 nM to >3.2 μM.

Determination of Anti-HIV Activity in the Presence of Human Serum

The above antiviral assay was performed in 96-well tissue culture platescontaining 50% human serum (HS) (Sigma) plus 10% FBS (Gibco/BRL, GrandIsland, N.Y.). Compounds were dissolved in DMSO, diluted at half logconcentrations in DMSO, then transferred to media without serum at fourtimes the final concentration. These solutions were added to 96-wellplates at 50 μL per well, in triplicate. Cells were separately infectedwith 0.003 MOI of HIV-1 at 1×10⁶ cells/mL for 1 hour, washed twice toremove unadsorbed virus and resuspended to 2×10⁵ cells/mL of mediawithout serum. The cell suspension (50 μL) was seeded at 1×10⁴ cells perwell. Uninfected cells were included as control. Final DMSOconcentration in all wells was 0.5% including uninfected and infectedcontrol wells. Cultures were incubated for 5 days in a CO₂ incubator at37° C. EC₅₀ values were measured using MTT uptake as described above.

When tested by the above method, compounds of the present inventionexhibit EC₅₀ in the range of 5 nM to >3.2 μM.

Generation of HIV-1 Resistant to ABT-378/r (A17) by in vitro Passage

MT4 cells (2×10⁶) were infected with pNL4-3 at an MOI of 0.03 for 2 h,washed, then cultured in the presence of ABT-378 and ritonavir atconcentration ratio of 5:1. The concentration of ABT-378 and ritonavirused in the initial passage was 1 nM and 0.2 nM respectively. Viralreplication was monitored by determination of p24 antigen levels in theculture supernatant (Abbott Laboratories), as well as by observation forany cytopathic effect (CPE) present in the cultures. When p24 antigenlevels were positive, the viral supernatant was harvested for theproceeding passage. Following each passage, the drug concentrations inthe subsequent passage were gradually increased. After 5 months ofselection, 1.5 μM of ABT-378 can be used in the final passage. The A17virus was generated after 17 passages of pNL43 in the presence ofABT-378 and ritonavir at concentration ratio of 5:1.

When tested by the above method, compounds of the present inventioninhibit the A17 virus with EC₅₀ in the range of 0.3 nM to >3.2 μM.

Synthetic Methods

Abbreviations which have been used in the descriptions of the schemesand the examples that follow are: DMF is N,N-dimethylformamide, DMSO isdimethylsulfoxide, THF is tetrahydrofuran, NMMO is 4-methylmorpholineN-oxide, HOBT is 1-hydroxybenzotriazole hydrate, DCC is1,3-dicyclohexylcarbodiimide, EDAC is1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, DMAP is4-(dimethylamino)pyridine, TFA is trifluoroacetic acid, DEPBT is3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one, DPPA isdiphenylphosphoryl azide, NMM is N-methylmorpholine, DIBAL is diisobutylaluminum hydride, EtOAc is ethyl acetate and TBAF is tetrabutyl ammoniumfluoride.

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes whichillustrate the methods by which the compounds of the invention may beprepared. Starting materials can be obtained from commercial sources orprepared by well-established literature methods known to those ofordinary skill in the art. The groups A, X, Y, L, B, R^(A), R¹, R², R³,R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R₁₀₄, R₁₀₅, R₁₀₆, R₁₀₇,R₁₀₈, R_(a), R_(b), R_(c), Z₁, Z₂, M, M′, m, m′, m″, t, r and n are asdefined above unless otherwise noted below.

This invention is intended to encompass compounds having formula (I),(II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII) or(XIII), when prepared by synthetic processes or by metabolic processes.Preparation of the compounds of the invention by metabolic processesincludes those occurring in the human or animal body (in vivo) orprocesses occurring in vitro.

Compounds of the invention can be prepared according to the methodsdescribed in Schemes 1-8 as shown below.

Compounds of formula (1) wherein P₁ is an N-protecting group, forexample 1-tert-butyloxycarbonyl or benzyloxycarbonyl, can be treatedwith a dialkyl malonate and a base in an alcoholic solvent such as, butnot limited to, methanol or ethanol, at a temperature of about −15° C.to about 30° C. to give compounds of formula (2), wherein P₂ is acarboxyl protecting group, for example ethyl, methyl, benzyl,tert-butyl, and the like. Examples of the dialkyl malonate are, but arenot limited to, diethyl malonate, dimethyl malonate or dibenzylmalonate. Examples of the base include, but are not limited to, sodiummethoxide, sodium ethoxide and sodium tert-butoxide.

Compounds of formula (2) can be isolated or reacted in-situ with analkylating agent of formula R³X, wherein X is F, Br, Cl or I, and thelike, in the presence of a base, in a solvent such as ethanol, methanol,THF, dioxane, DMF, or mixtures thereof, at a temperature from about 25°C. to about 80° C., to give compounds of formula (3). Examples of thebase include, but are not limited to, sodium methoxide, sodium ethoxideand sodium tert-butoxide, NaNH₂, lithium bis(trimethylsilyl)amide andlithium diisopropylamide.

Compounds of formula (3) can be converted to compounds of formula (4) by(a) reacting compounds of formula (3) with a base, in a solvent such as,but not limited to, THF, DMF, methanol, ethanol or water, and mixturesthereof, at a temperature from about 25° C. to about 100° C., and (b)heating the product of step (a) at reflux in a high boiling solvent suchas, but not limited to, benzene, toluene, xylene, DMF or acetic acid.Examples of the base include, but are not limited to, lithium hydroxide,sodium hydroxide, potassium hydroxide and potassium carbonate.

Transformation of compounds of formula (4) to compounds of formula (6),wherein P₃ is a hydroxyl protecting group (for example,tert-butyldimethyl silyl) can be achieved in a one-step or stepwisemanner by (a) contacting compounds of formula (4) with a first base in asolvent such as, but not limited to, N-methylpyrrolidinone, DMF, THF,dioxane at a temperature from about 0° C. to about 50° C., and (b)contacting the product of step (b) with a silylating agent and a secondbase in an inert solvent such as, but not limited to, ethyl acetate,THF, dichloromethane, DMF, NMP, acetonitrile, isopropyl acetate ortoluene, and the like, at a temperature from about −10° C. to about 60°C. Examples of the first base include, but are not limited to, inorganicbases such as sodium hydroxide, lithium hydroxide, potassium hydroxide,and the like, optionally in the presence of4-N,N-(dimethylamino)pyridine (DMAP). Examples of the second baseinclude, but are not limited to, organic amine bases such as imidazole,1-methylimidazole, 2-methylimidazole, 2-isopropylimidazole,4-methylimidazole, 4-nitroimidazole, pyridine,N,N-dimethylaminopyridine, 2,6-lutidine, 1,2,4-triazole, pyrrole,3-methylpyrrole, triethylamine or N-methylmorpholine and the like.Examples of the silylating agent include, but are not limited to,trimethylsilyl chloride, trimethylsilyl triflate,tert-butyldimethylsilyl chloride, and tert-butyldimethylsilyl triflate.

Compounds of formula (6) can be converted to compounds of formula (7),wherein P₄ is an N-protecting group (for example benzyloxy carbonyl), ina one-step or stepwise manner, by (a) treating compounds of formula (6)with diphenylphosphoryl azide and a base such as, but not limited to,triethylamine, diisoproylethylamine, N-methylmorpholine, and the like ina solvent, or mixture of solvents, such as xylene, toluene, benzene orDMF, and the like, at a temperature from about 80° C. to about 150° C.,(b) treating the product of step (b) with an alcohol at a temperaturefrom about 80° C. to about 150° C., in a solvent, in a solvent, ormixture of solvents, such as xylene, toluene, benzene or DMF, and thelike, and (c) treating the product of step(b) with a desilylating agentin a solvent, or mixture of solvents, such as THF, DMF, ethyl acetate,dichloromethane, acetone, acetonitrile, methanol or diethyl ether, andthe like, at a temperature from about 0° C. to about 50° C. Examples ofthe alcohol include, but are not limited to, tertbutyl alcohol andbenzyl alcohol. Examples of the desilylating agent include, but are notlimited to, tetrabutyl ammonium fluoride, acetic acid, formic acid, HCl,HF and citric acid.

Removal of the P₄ benzyloxy carbonyl group of (7) (for example, usinghydrogen and a hydrogenation catalyst or Pd/C and a formic acid salt(for example, ammonium formate and the like) or Pd/C and formic acid andthe like) provides (8). Examples of the hydrogenation catalyst include,but are not limited to, Pd/C, Raney nickel, platinum metal and itsoxides.

Compounds of formula (8) are reacted with carboxylic acids of formula(9) and an activating agent, optionally in the presence of1-Hydroxy-7-azabenzotriazole (HOAT), 1-hydroxybenzotriazole hydrate(HOBT) or 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (HOOBT), and optionallyin the presence of an inorganic base (for example, sodium bicarbonate,sodium carbonate, potassium bicarbonate, potassium carbonate, sodiumhydroxide, potassium hydroxide, and the like) in an inert solvent (forexample, 1:1 ethyl acetate/water or sopropyl acetate/water ortoluene/water or THF/water and the like) at about room temperature, oran organic amine base (for example, imidazole, 1-methylimidazole,2-methylimidazole, 2-isopropylimidazole, 4-methylimidazole,4-nitroimidazole, pyridine, 4-(dimethylamino)pyridine, 1,2,4-triazole,pyrrole, 3-methylpyrrole, triethylamine or N-methylmorpholine and thelike) in an inert solvent (for example, ethyl acetate, isopropylacetate, THF, toluene, acetonitrile, DMF, dichloromethane and the like)at a temperature from about 0° C. to about 50° C. to provide compound(10). Examples of the activating agent include, but are not limited to,1,1′-carbonyldiimidazole (CDI), 1,3-dicyclohexylcarbodiimide (DCC),1,3-diisopropylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC),DEPBT (3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one),benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphoniumhexafluorophosphate(PyBOP), and 1,3-di-tert-butylcarbodiimide. Alternatively, a salt or anactivated ester derivative of acid (9) (for example, the acid chloride,prepared by reaction of the carboxylic acid with thionyl chloride inethyl acetate or THF or oxalyl chloride in toluene/DMF) can be reactedwith (8).

Removal of tert-butoxycabonyl group can be accomplished by treatingcompounds of formula (10) with an acid (for example, trifluoroaceticacid, hydrochloric acid, methanesulfonic acid, toluenesulfonic acid,sulfuric acid, aluminum chloride and the like) in an inert solvent (forexample, dioxane, dichloromethane, chloroform, methanol, THF,acetonitrile and the like) at a temperature from about 0° C. to aboutroom temperature, to provide (11).

Compounds of formula (11) can be reacted with acids of formula (12), orits salts, using the conditions for the transformation of (8) to (10),to provide compounds of formula (13).

Protected amino acids of formula (14), wherein P₅ is lower alkyls, P₆and P₇ are N-protecting groups (preferably, P₆ and P₇ are benzyl) isreacted with sodioacetonitrile (formed in-situ from acetonitrile and abase such as NaNH₂) or lithioacetonitrile (formed in-situ fromacetonitrile and a base such as lithium bis(trimethylsilyl)amide, orlithium diisopropylamide, and the like) in a solvent, or mixtures ofsolvents, such as acetonitrile or THF, and the like, at a temperature ofabout −40° C. to provide ketonitrile (15). Addition of an organometallicreagent of formula R⁶MX, wherein M is a metal such as magnesium, and Xis Cl, Br or I, in aninert solvent such as, but not limited to,dichloromethane, THF, diethyl ether, methyl tert-butyl ether, at atemperature from about 0° C. to about room temperature. Examples of theorganometallic reagent include, but are not limited to, benzyl magnesiumchloride and methylmagnesium bromide. Reduction of (16) to compounds offormula (17) can be accomplished by reaction with a reducing agent in aninert solvent, or mixtures of solvents, such as ethyl acetate, THF,dichloromethane, ethyl acetate, diethyl ether and the like, at atemperature from about −10° C. to about room temperature. Examples ofreducing agents include, but are not limited to, hydrogen in thepresence of a catalyst (for example, Pd/C, Raney nickel, platinum metalor its oxides and the like), metallic hydrides such as lithium aluminumhydride and sodium borohydride. The amino group can subsequently beprotected to provide compound (18), wherein P₈ is tert-butoxycarbonyl,by conditions that are well known in the art.

N-Debenzylation of compounds of formula (18) wherein P₆ and P₇ arebenzyl to provide compounds of formula (19) can be achieved using theconditions for the transformation of compounds of formula (7) tocompounds of formula (8).

Conversion of compounds of formula (19) to compounds of formula (23) canbe achieved using the conditions for the transformation of compounds offormula (8) to compounds of formula (13)

Amino acid esters of formula (24), wherein P₂ is lower alkyls (forexample methyl, ethyl, tert-butyl and the like), can be treated with asuitably protected aldehyde of formula (25) (for example, P₁₀ and P₁₁together with the nitrogen atom they are attached, form a phthalimidogroup) in the presence of a reducing agent, optionally under acidicconditions (for example, in the presence of acetic acid or hydrochloricacid), in an inert solvent, or mixture of solvents, such as methylsulfoxide, methanol, dichloromethane, and the like, at a temperaturefrom about room temperature to about 50° C., to provide compounds offormula (26). Examples of the reducing agent include, but are notlimited to, sodium triacetoxyborohydride, sodium borohydride, sodiumcyanoborohydride, and BH₃-pyridine.

Removal of the phthalimido group can be achieved by treatment withhydrazine in a suitable solvent such as ethanol and the like, at atemperature of about room temperature to about 100° C., to providecompounds of formula (27).

Compounds of formula (27) can be converted to compounds of formula (28)by (a) treating compounds of formula (27) with an aldehyde havingformula R⁹CHO, optionally in the presence of a drying agent (forexample, magnesium sulfate, silica gel and the like) in an inertsolvent, or mixture of solvents, such as dichloromethane, benzene,toluene, methanol, ethanol, methyl sulfoxide, and the like, at atemperature from about room temperature to about 100° C., and (b)reacting the product of step (a) with a reducing agent at about roomtemperature. Examples of the reducing agent include, but are not limitedto, sodium triacetoxyborohydride, sodium borohydride, sodiumcyanoborohydride, and BH₃-pyridine.

The diamine of formula (28) can be treated with a carbonylating agent inan inert solvent, or mixture of solvents, such as dichloromethane, 1,2dichloroethane, toluene, acetonitrile, and the like, at a temperaturefrom about room temperature to about 100° C., to provide compounds offormula (29). Examples of the carbonylating agent include, but not arelimited to, 4-nitrophenyl carbonate, phosphene, diphosgene, triphosgene,carbonyl diimidazole and disuccinimidyl carbonate.

Conversion of compounds of formula (29) to the corresponding acidshaving formula (30) can be achieved by acid hydrolysis (for exampleacetic acid, trifluoroacetic acid, toluenesulfonic acid, formic acid,hydrochloric acid and the like) or base hydrolysis (for example sodiumhydroxide, potassium hydroxide, lithium hydroxide, cesium carbonate, andthe like) in a solvent, or mixture of solvents such as DMF, toluene,benzene, dichloromethane, ethyl acetate, water, methanol and the like,at a temperature from about 0° C. to about 100° C.

Amino acid esters having formula (24), wherein P₂ is lower alkyls (forexample, methyl, ethyl, tert-butyl and the like) can be treated withcompounds of formula R³⁰C(O)CH₂X, wherein R³⁰ is lower alkyls and X isBr, Cl, or I, in an inert solvent, or mixture of solvents, such as DMF,dichloromethane, 1,2-dichloroethane, acetonitrile, toluene, benzene,diethyl ether and the like, at a temperature of about room temperatureto about 50° C., to provide (31).

Compounds of formula (31) can be converted to compounds of formula (32)by (a) treating with compounds of formula XSO₂NCO (for examplechlorosulfonyl isocyanate), wherein X is Br, Cl, or I, in an inertsolvent, or mixture of solvents, such as dichloromethane,1,2-dichloroethane, dioxane, toluene, DMF, THF diethyl ether and thelike, at a temperature from about −10° C. to about room temperature, and(b) treating the product of step (a) with water at about roomtemperature. Alternatively, (31) can be reacted with a carbonylatingagent such as, but not limited to, 4-nitrophenyl carbonate, phosphene,diphosgene, triphosgene, carbonyl diimidazole, disuccinimidyl carbonate,followed by reaction with ammonia.

Cyclization of the compounds of formula (32) to provide compounds offormula (33) can be achieved be treating with an organic amine base suchas triethylamine, diisopropylethylamine, imidazole, pyridine,N-methylmorpholine and the like, or an inorganic base such as sodiumbicarbonate, sodium carbonate, cesium carbonate and the like, in aninert solvent, or mixture of solvents, such as methanol, ethanol, DMF,dioxane, xylene, THF and the like, at a temperature from about roomtemperature to about 100° C.

Imides of formula (33) can be converted to compounds of formula (35) by(a) deprotonation with a base in an inert solvent, or mixture ofsolvents, such as DMF, THF, diethyl ether, tert-butyl methyl ether, andthe like, at a temperature from about −78° C. to about 0° C., and (b)treating product of step (a) with an alkyl halide of formula (34),wherein X is Cl, Br or I, at a temperature from about room temperatureto about 100° C. Examples of the base include, but are not limited to,sodium hydride, potassium hydride, lithium diisopropyl amide, lithiumbis(trimethylsilyl)amide.

Alternatively, compounds of formula (33) can be converted to compoundsof formula (35) by treating with an alcohol having formula R¹¹CH₂OH, inthe presence of triphenylphosphine and diethyl azodicarboxylate, in aninert solvent such as dichloromethane, THF, dioxane or DMF, at atemperature of about 0° C. to about 25° C.

Conversion of compounds of formula (35) to compounds of formula (36) canbe achieved by using the conditions for the transformation of compoundsof formula (29) to compounds of formula (30).

Protected amino acids of formula (37), wherein P₁₂ is an N-protectinggroup (for example benzyloxycarbonyl, benzyl, tert-butyloxycarbonyl, andthe like) and R³¹ is hydrogen or lower alkyls (for example, methyl,ethyl and the like), can be converted to compounds of formula (38) by(a) treating with a reducing agent in an inert solvent such asdichloromethane, diethyl ether, THF, tert-butyl methyl ether, and thelike, at a temperature from about −78° C. to about room temperature, and(b) treating the product of step (a) with an oxidizing agent in an inertsolvent, such as dichloromethane, diethyl ether, THF, tertbutyl methylether, and the like, at a temperature from about 0° C. to about roomtemperature. Examples of the reducing agent include, but are not limitedto, lithium aluminum hydride, lithium borohydride, sodium borohydrideand diisobutylaluminum hydride. Examples of the oxidizing agent include,but are not limited to, oxalyl chloride/methyl sulfoxide/triethylamine,Jones reagent, Cr(VI) reagents such as pyridinium chlorochromate,SO₃/pyridine, MnO₂ and KMnO₄.

Compounds of formula (38) can condense with itself, or an aldehyde offormula P₁₃N(H)CH(R³)CHO (prepared from the corresponding carboxylicacids or esters using the conditions for the transformation of (37) to(38)), wherein P₁₃ is a N-protecting group, and may be the same as ordifferent from P₁₂, to give a diols having formula (39). Thetransformation can be accomplished with vanadium(III) chloride-THFcomplex and zinc at about room temperature in an inert solvent, such asdichloromethane, THF, diethyl ether, 1,2-dichloroethane, and the like.

N-Deprotection of compounds of formula (39) can be performed in astepwise manner (if P₁₂ is different from P₁₃) or in one step (if P₁₂ isthe same as P₁₃) using the conditions for the transformation of (7) to(8), if the N-protecting groups are benzyl or tert-benzyloxycarbonyl, orusing the conditions for the transformation of (10) to (11), if the Nprotecting groups are tert-butyloxycarbonyl.

The compounds of formula (41) can be prepared from (40) and carboxylicacids of formula (12), or its salt, using standard peptide couplingconditions (see the conditions for the transformation of (8) to (10)).The compounds of formula (41) can be converted to compounds of formula(42) by (a) treating with a thiocarbonylating agent in an inert solventsuch as THF, dichloromethane, 1,2-dichloroethane, diethyl ether,toluene, xylene, and the like, at a temperature from about roomtemperature to about 100° C., and (b) treating products of step (b) withtributyltin hydride and 2,2′ azobisisobutyronitrile in an inert solvent,such as THF, dichloromethane, 1,2-dichloroethane, diethyl ether,toluene, xylene, and the like, at a temperature from about roomtemperature to about 150° C. Examples of the thiocarbonylating agentinclude, but are not limited to, thiocarbonyldiimidazole, andthiophosgene/4-(dimethylamino)pyridine.

Compounds of formula (43) wherein X is Br, I, Cl or triflate can beconverted to compounds of formula (44), wherein P₁₃ is a hydroxylprotecting group (for example, trialkyl silyl, methoxymethyl, and thelike) by using the conditions for the transformation of (5) to (6).Treatment of compounds of formula (44) with compounds of formula Y—X¹,wherein Y is aryl or heteroaryl, and X¹ is Br, I, Cl, B(OH)₂, orSn(lower alkyl)₃, and a palladium catalyst, optionally in the presenceof a base (for example cesium carbonate, triethylamine, and the like),and optionally in the presence of CuI, provide compounds of formula(45). Examples of the palladium catalyst include, but are not limitedto, tetrakis(triphenylphosphine)Pd(0),dichlorobis(triphenylphosphine)Pd(II), Pd on carbon, Pd(OAc),tris(dibenzylideneacetone)dipalladium(0), or any of the above withadditional phosphine ligands such as, 2-(dicyclohexylphosphino)biphenylor 2-(di-tert-butylphosphino)biphenyl. Compounds of formula (45) can beconverted to compounds of formula (7), wherein R³ is arylalkyl andwherein the aryl moiety of the arylalkyl is substituted by aryl orheteroaryl, by treatment with a desilylating agent such as, but notlimited to, tetrabutyl ammonium fluoride, acetic acid, formic acid, HCl,HF and citric acid in a solvent, or mixture of solvents, such as THF,DMF, ethyl acetate, dichloromethane, acetone, acetonitrile, methanol ordiethyl ether, and the like, at a temperature from about 25° C. to about50° C.

Compounds of formula (47) wherein P₉ is tert-benzyloxycarbonyl, can beobtained from compounds of formula (46) using conditions well known inthe art. The compounds of formula (47) can be converted to compounds offormula (48) by treatment with excess 2,2-dimethoxypropane in thepresence of an acid (for example, toluenesulfonic acid, acetic acid,sulfuric acid, and the like) at a temperature from about 0° C. to aboutroom temperature, optionally in the presence of an inert solvent such asdichloromethane, toluene, benzene, acetone, and the like. Transformationof (48) to compounds of formula (49), wherein Y is aryl or heteroaryl,can be accomplished by the conditions for the conversion of (44) to(45). Compounds of formula (49) can be converted to compounds of formula(50) by acid hydrolysis (for example acetic acid, trifluoroacetic acid,toluenesulfonic acid, formic acid, hydrochloric acid and the like) insolvent, or mixture of solvents, such as water, methanol, isopropylalcohol, ethanol, dichloromethane, THF, acetonitrle, toluene, benzene,1,2-dichloroethane, ethyl acetate, and the like, at a temperature fromabout room temperature to about 100° C. Compounds of formula (50) can bede-protected by employing the conditions for the conversion of (7) to(8) as illustrated in scheme 1, to provide compounds of formula (19)wherein R³ is arylalkyl and wherein the aryl moiety of the arylalkyl issubstituted with aryl or heteroaryl.

Compounds of formula (I) wherein R⁴ is H and R⁵ is OR¹⁶ wherein R¹⁶ is Hcan be converted to compounds of formula (52) wherein t is 1, and each Mis independently hydrogen, alkyl or benzyl, and wherein both M can bethe same or different via the following two step reaction: (a) reactingthe starting material with an alkyl sulfide having formulaH—CHR₁₀₄—SR₉₀, wherein R₉₀ is alkyl, an oxidizing agent, and with orwithout a base in a solvent to provide compounds of formula (51), and(b) reaction compounds of formula (51) with phosphoric acid to providecompounds of formula (Ia) wherein both M are hydrogen, or with thecorresponding monoester or diester of the phosphoric acid to providecompounds of formula (52) wherein one or both M are alkyl or benzyl andthe other is hydrogen and wherein both M can be the same or different.

Step (a) can be can be performed in a solvent such as, but is notlimited to, acetonitrile or tetrahydrofuran, at a temperature from about−10° C. to about 50° C. Examples of alkyl sulfides include, but are notlimited to, methyl sulfide, ethyl sulfide, butylsulfide and t-butylmethyl sulfide. Examples of suitable oxidizing agents include, but arenot limited to, benzoyl peroxide, N-chlorosuccinimide andN-chloro-N-methylacetamide. Examples of bases include, but are notlimited to, triethylamine, diisopropylethylamine, tributylamine,morpholine and 1-methylimidazole. Alternatively, the thioethers offormula (51) can be prepared from an alkyl sulfoxide, such as dimethylsulfoxide, and an acid anhydride such as acetic anhydride in a solventsuch as acetonitrile, acetic acid or dimethyl sulfoxide at a temperaturefrom about 20° C. to about 50° C. Compounds of formula (51) can also beprepared by treatment of compounds of formula (I) wherein R⁴ is H and R⁵is OH, with a haloalkyl alkyl sulfide having formula X—CHR₁₀₄—SR₉₀,wherein X is Cl, Br, F or I, in the presence of a base in a solvent andoptionally in the presence of a silver salt such as AgNO₃. An example ofa suitable haloalkyl alkyl sulfide includes, but is not limited to,chloromethyl methyl sulfide. Examples of suitable bases include, but arenot limited to metal hydrides (for example sodium hydride and the like),lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, andpotassium bis(trimethylsilyl)amide. The reaction can be performed in asolvent such as, but not limited to, tetrahydrofuran,N,N-dimethylformamide or diethyl ether at a temperature from about −78°C. to about the reflux temperature of the solvent employed.

Step (b) is generally performed by contacting compounds of formula (51)with reagent 1, and with or without a dehydrating reagent, in a solvent.Examples of reagents 1 include, but are not limited to,N-iodosuccinimide, N-chlorosuccinmide, N-bromosuccinimide, iodoniumdicollidine triflate, methyl iodide, AgNO₃ and trimethylsilyl chloride.Examples of dehydrating agents include, but are not limited to,molecular sieves, magnesium sulfate, Na₂SO₄, and K₂CO₃. The reaction canbe performed in a solvent such as, but not limited to, ethyl acetate,tetrahydrofuran, N,N-dimethylformamide or acetonitrile at a temperaturefrom about −40° C. to about room temperature.

Using similar methodology, compounds of formula (I) wherein R⁴ is OH andR⁵ is H can be transformed to compounds of formula (53) wherein t is 1,and each M is independently hydrogen, alkyl or benzyl and wherein both Mcan be the same or different.

Compounds of formula (I) wherein R¹⁵ is formula (XVI), Z₁ is O, Z₂ is O,W is P, Q is O, t is 1, and at least one M is hydrogen and the other ishydrogen, alkyl or benzyl, can be converted to the corresponding mono ordibasic salts wherein (a) t is 1, one of M's is a movalentcation (forexample, sodium, potassium, ammonium, triethylammonium and the like),and the other is hydrogen, alkyl or benzyl, or both M are movalentcation (for example, sodium, potassium, ammonium, triethylammonium andthe like) and that both M can be the same or different, or (b) t is 0, Mis a monovalent or divalent cation, (for example calcium, barium,magnesium and the like) by reacting with about half, one or twoequivalents of a variety of inorganic and organic bases, either in situor after isolation of the compound of formula (D wherein R¹⁵ is formula(XVI), Z₁ is O, Z₂ is O, W is P, Q is O, t is 1, and at least one M ishydrogen and the other is hydrogen, alkyl or benzyl, from the reactionmixtures, it is understood that when t is 0, the oxygen that is adjacentto (M)_(t) is a charged specie, and that the counter ion may be locatedelsewhere in the same molecule or the net negative charge is balanced byanother molecule of compound of formula (I) that is bearing a net chargeof −1. The salts can be obtained via a one step reaction or stepwisefrom compounds of formula (I) wherein R¹⁵ is formula (XVI), Z₁ is O, Z₂is O, W is P, Q is O, t is 1, and at least one M is hydrogen and theother is hydrogen, alkyl or benzyl. The reaction can be performed inaqueous solvent medium or in a suitable organic solvent such as methanolor ethanol. Typically the reaction is carried out at a temperature fromabout −10° C. to about 70° C. for about 5 minutes to about 48 hours.Upon evaporation of the solvent, the desired solid salt is obtained withor without further purification such as chromatography.

The present invention will now be described in connection with certainpreferred embodiments which are not intended to limit its scope. On thecontrary, the present invention covers all alternatives, modifications,and equivalents as can be included within the scope of the claims. Thus,the following examples, which include preferred embodiments, willillustrate the preferred practice of the present invention, it beingunderstood that the examples are for the purpose of illustration ofcertain preferred embodiments and are presented to provide what isbelieved to be the most useful and readily understood description of itsprocedures and conceptual aspects.

Compounds of the invention were named by ACD/ChemSketch version 4.01(developed by Advanced Chemistry Development, Inc., Toronto, ON, Canada)or were given names consistent with ACD nomenclature.

EXAMPLE 1methyl(1S,4R,6S,7S,10S)-7-benzyl-1,10-ditert-butyl-6-hydroxy-2,9,12-trioxo-4-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamateEXAMPLE 1Atert-butyl(1S)-1-{(2S)-5-oxo-4-[4-(2-pyridinyl)benzyl]tetrahydro-2-furanyl}-2-phenylethylcarbamate

A solution of tert-Butyl(1S)-1-[(2R)-oxiran-2-yl]-2-phenylethylcarbamate (10.0 g, 38.0 mmol) anddiethyl malonate (5.8 ml, 38.2 mmol) in ethanol (30 mL) at 0° C. wastreated with sodium ethoxide (17 mL, 21% in ethanol) over 10 minutes.The reaction was warmed to 25° C. and stirred for 2 hours, treated withadditional diethyl malonate (0.58 mL, 3.4 mmol) and stirred for 1 hour.The reaction was cooled to 0° C., and solid2-[4-(bromomethyl)phenyl]pyridine (9.43 g, 38.0 mmol) was added in fourincrements over 10 minutes. To this suspension was added ethanol (20 mL)and the mixture was stirred at 25° C. for 16 hours. The reaction mixturewas treated with LiOH monohydrate (4.6 g, 109.6 mmol) solution in water(30 mL), stirred at 25° C. for 16 hours, cooled to 0° C., adjusted to pH5 by addition of 4N HCl and partitioned between dichloromethane andwater. The organic phase was washed with brine and dried over MgSO₄,filtered and concentrated. A solution of the concentrate in toluene (100mL) was heated at reflux for 16 hours, cooled to 25° C. and concentratedto afford the title compound (21.4 g).

EXAMPLE 1B(4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(dimethyl)silyl]oxy}-6-phenyl-2-[4-(2-pyridinyl)benzyl]hexanoicacid

A solution of the product from Example 1A (21.4 g) in dioxane (100 mL)was treated with sodium hydroxide solution (57 mL, 1N), stirred at 25°C. for 30 minutes and concentrated. The concentrate was cooled to 0° C.,and acidified to pH 5 with 4N HCl. The mixture was partitioned betweendichloromethane and water, and the organic phase layer was washed withbrine, dried over MgSO₄, filtered and concentrated. A solution of theresidue in N,N-dimethylformamide (100 mL) was treated with imidazole (21g, 308.5 mmol) and t-butyldimethylsilyl chloride (23 g, 152.6 mmol),stirred at 25° C. for 16 hours and concentrated. The residue wascombined with ice and acidified with 4N HCl to pH 3. Ethyl acetate (50mL) was added to permit stirring during the acidification. The mixturewas extracted with ethyl acetate, washed with brine, dried over MgSO₄,filtered, and concentrated. The residue was chromatographed on silicagel eluting with a gradient of 200%-100% ethyl acetate in chloroform,followed by elution with 5% methanol in ethyl acetate to give the titleproduct (11.3 g, 49% yield).

EXAMPLE 1C Benzyl(1S,3S,4S)-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentylcarbamate

A solution of the product from Example 1B (11.3 g, 18.7 mmol) in toluene(190 mL) was treated with DPPA (8.1 mL, 37.6 mmol) and triethylamine(5.2 mL, 37.3 mmol), heated at reflux for 2 hours, treated with benzylalcohol (5.8 mL, 56.0 mmol), heated at reflux for an additional 16hours, cooled to 25° C. and concentrated. The residue was treated with asolution of TBAF in THF (94 mL, 1N), stirred at 25° C. for 40 hours andconcentrated. The mixture was partitioned between ethyl acetate andwater. The organic phase was washed with brine, dried over MgSO₄,filtered and concentrated. The residue was chromatographed on silica geleluting with 50% ethyl acetate in chloroform to give 4.2 g (38% yield)of the lower Rf product by TLC (35% ethyl acetate in dichloromethane).

EXAMPLE 1D Benzyl(1R,3S,4S)-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentylcarbamate

A solution of the product from Example 1B (11.3 g, 18.7 mmol) in toluene(190 mL) was treated with DPPA (8.1 mL, 37.6 mmol) and triethylamine(5.2 mL, 37.3 mmol), heated at reflux for 2 hours, treated with benzylalcohol (5.8 mL, 56.0 mmol), heated at reflux for an additional 16hours, cooled to 25° C. and concentrated. The residue was treated with asolution of tetrabutylammonium fluoride in THF (94 mL, 1N), stirred at25° C. for 40 hours and concentrated. The mixture was partitionedbetween ethyl acetate and water. The organic phase was washed withbrine, dried over MgSO₄, filtered and concentrated. The residue waschromatographed on silica gel eluting with 50% ethyl acetate inchloroform to give 2.6 g (23% yield) of the higher Rf product by TLC(35% ethyl acetate in dichloromethane).

EXAMPLE 1Etert-butyl(1S,2S,4R)-4-amino-1-benzyl-2-hydroxy-5-[4-(2-pyridinyl)phenyl]pentylcarbamate

A solution of the product from Example 1D (2.6 g, 4.4 mmol) in a mixtureof methanol (22 mL) and ethyl acetate (22 mL) was treated with Pd(OH)₂on carbon (0.8 g, 20% Pd by wt.) and HCl solution (1.0 mL, 4N indioxane), stirred under a hydrogen atmosphere (balloon pressure) at 25°C. for 16 hours, filtered through celite®, rinsed with methanol andconcentrated to give the title product (1.7 g) as the hydrochloridesalt.

EXAMPLE 1F (2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoic acid

A solution of L-tert-Leucine (25 g, 190.58 mmol) in a mixture of dioxane(100 mL) and aqueous NaOH solution (315 mL, 2N) was treated dropwisewith methyl chloroformate (29.3 mL, 379.19 mmol), keeping the internaltemperature below 50° C. The mixture was warmed to 60° C. and stirredfor 18 hours, cooled to 25° C. and extracted with dichloromethane. Theaqueous phase was cooled to 0° C. and the pH was adjusted to about 1-2with concentrated HCl. The mixture was partitioned between ethyl acetateand water. The combined organic extracts were washed with brine, driedover MgSO₄, filtered and concentrated. A solution of the concentrate inether was treated with hexanes to afford the crystalline product (33.22g, 92% yield), which was collected by filtration.

EXAMPLE 1Gtert-butyl(1S,2S,4R)-1-benzyl-2-hydroxy-4-({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-5-[4-(2-pyridinyl)phenyl]pentylcarbamate

A solution of the product of Example 1E (1.7 g) in THF (33 mL) wastreated with the product of Example 1F (0.81 g, 4.3 mmol), DEPBT (1.5 g,5.0 mmol), and N,N-diisopropylethylamine (2.9 mL, 16.6 mmol), stirred at25° C. for 16 hours, and partitioned between ethyl acetate and 10%Na₂CO₃ solution. The organic phase was washed with additional 10% Na₂CO₃solution and brine, dried over MgSO₄, filtered and concentrated. Theresidue was chromatographed on silica gel eluting with 0-100% ethylacetate/dichloromethane to give the title compound (1.55 g, 74% yield).

EXAMPLE 1Hmethyl(1S)-1-[({(1R,3S,4S)-4-amino-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution of the product of Example 1G (1.55 g, 2.45 mmol) indichloromethane (12.5 mL) was treated with trifluoroacetic acid (12.5mL), stirred at 25° C. for 1 hour and concentrated. The concentrate waspartitioned between ethyl acetate and saturated NaHCO₃ solution. Theorganic phase extract was washed with brine, dried over MgSO₄, filteredand concentrated to give the title compound (1.4 g) which was usedwithout further purification.

EXAMPLE 1Imethyl(1S,4R,6S,7S,10S)-7-benzyl-1,10-ditert-butyl-6-hydroxy-2,9,12-trioxo-4-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate

A solution of the product of Example 1H (0.18 g, 0.33 mmol) in THF (3.3mL) was treated with the product of Example 1F (0.11 g, 0.60 mmol),DEPBT (0.15 g, 0.50 mmol), and N,N-diisopropylethylamine (0.29 mL, 1.66mmol), stirred at 25° C. for 16 hours, and partitioned between ethylacetate and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with0%-75% ethyl acetate in chloroform to give the title product (0.19 g,81% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.75 (s, 9 H), 0.78 (s, 9H), 1.28 (m, 2 H), 1.55 (m, 1 H), 2.70 (m, 4 H), 3.55 (d, J=11.77 Hz, 6H), 3.85 (m, 3 H), 4.15 (m, 1 H), 4.80 (d, J=5.15 Hz, 1 H), 6.75 (d,J=9.19 Hz, 1 H), 6.86 (d, J=9.56 Hz, 1 H), 7.13 (m, 5 H), 7.22 (d,J=8.46 Hz, 2 H), 7.32 (m, 1 H), 7.52 (d, *8.82 Hz, 1 H), 7.88 (m, 5 H),8.64 (d, j=4.41 Hz, 1 H).

EXAMPLE 2methyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate

Method A

EXAMPLE 2Atert-butyl(1S,2S,4S)-4-amino-1-benzyl-2-hydroxy-5-[4-(2-pyridinyl)phenyl]pentylcarbamate

A solution of the product of Example 1C (4.2 g, 7.0 mmol) in a mixtureof methanol (35 mL) and ethyl acetate (35 mL) was treated with Pd(OH)₂on carbon (1.4 g, 20% Pd by wt.) and HCl solution (1.8 mL, 4N indioxane), and the reaction was stirred under a hydrogen atmosphere(balloon pressure) for 16 hours at 25° C. The reaction mixture wasfiltered through a bed of celite®, rinsed with methanol and concentratedto give the title compound as the hydrochloride salt (3.7 g).

EXAMPLE 2Btert-butyl(1S,2S,4S)-1-benzyl-2-hydroxy-4-({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-5-[4-(2-pyridinyl)phenyl]pentylcarbamate

A solution of the product of Example 2A (3.7 g, 7.4) in THF (75 mL) wastreated with the product from Example 1F (1.39 g, 7.4 mmol), DEPBT (3.3g, 11.0 mmol), and N,N-diisopropylethylamine (6.4 mL, 36.7 mmol),stirred at 25° C. for 16 hours, and partitioned between ethyl acetateand 10% Na₂CO₃ solution. The organic phase was washed with additional10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with33%-100% ethyl acetate in chloroform to give the title compound (3.5 g,75% yield).

EXAMPLE 2Cmethyl(1S)-1-[({(1S,3S,4S)-4-amino-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution of the product of Example 2B (3.5 g, 5.5 mmol) indichloromethane (40 mL) was treated with trifluoroacetic acid (20 mL),stirred at 25° C. for 1 hour, and concentrated. The concentrate waspartitioned between ethyl acetate and saturated NaHCO₃ solution. Theorganic phase was washed with brine, dried over MgSO₄, filtered andconcentrated to afford the crude product (3.19 g).

EXAMPLE 2Dmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate

A solution of the product of Example 2C (1.6 g, 3.0 mmol) in THF (30 mL)was treated with the product of Example 1F (0.57 g, 3.0 mmol), DEPBT(1.35 g, 4.5 mmol), and N,N-diisopropylethylamine (2.6 mL, 14.9 mmol),stirred at 25° C. for 3 hours and partitioned between ethyl acetate and10% Na₂CO₃ solution. The organic phase was washed with additional 10%Na₂CO₃ solution and brine, dried over MgSO₄ filtered and concentrated.The residue was chromatographed on silica gel eluting with 50% ethylacetate in chloroform, followed by. 5% methanol in chloroform to givethe title compound (1.59 g, 75% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm0.79 (s, 9 H), 0.82 (s, 9 H), 1.51 (m, 2 H), 2.51 (m, 1 H),2.72 (m, 3H), 3.49 (s, 3 H), 3.55 (s, 3 H), 3.63 (m, 1 H), 3.82 (d, J=9.93 Hz, 1H), 3.90 (d, J=9.56 Hz, 1 H), 4.04 (m, 2 H), 4.86 (d, J=5.88 Hz, 1 H),6.60 (d, J=9.93 Hz, 1 H), 6.78 (d, J=9.19 Hz, 1 H), 7.16 (m, 7 H), 7.31(m, 1 H), 7.54 (d, J=8.46 Hz, 1 H), 7.83 (m, 5 H), 8.63 (d, J=4.78 Hz, 1H).

Method B

A mixture of (2S)-2-[(methoxycarbonyl)amino]-3,3-dimethyl-butanoic acid(4.5 g, 23.7 mmol), HBTU (9.0 g, 23.7 mmol) and diisopropylethylamine(11.8 mL, 67.5 mmol) in ethyl acetate (120 mL) and acetonitrile (24 mL)was stirred at 25° C. for 1 hr, treated with the product of Example111-14 (12.1 g, 22.5 mmol) and stirred at room temperature overnight.The reaction mixture was filtered and the solid was washed with ethylacetate (90 mL). The isolated white solid was dissolved in acetonitrile(150 mL) at 70° C. After mixing at 70° C. for 1 hr, the solution wascooled down to room temperature and stirred for 2 hrs and filtered. Theisolated solid was washed with acetonitrile (80 mL) and dried to affordthe title compound as a white solid. Yield: 91%. ¹H NMR (DMSO-d₆) δ ppm0.79 (s, 9H), 0.81(s, 9H), 1.52(m, 2H), 2.51 (m, 1H), 2.72 (m, 3H), 3.48(s, 3H), 3.54 (s, 3H), 3.63 (m, 1H), 3.81 (d, J=8 Hz, 1H), 3.89 (d, J=8Hz, 1H), 4.00-4.20 (m, 2H), 4.85 (d, J=8 Hz, 1H), 6.58 (d, J=8 Hz, 1H),6.76 (d, J=8 Hz, 1H), 7.107.18 (m, 7H), 7.30 (m, 1H), 7.53 (m, 1H),7.81-7.87 (m, 5H), 8.60-8.62 (d, J=8Hz, 1H).

Method C

EXAMPLE 2-1(2S)-5-amino-2-(dibenzylamino)-1-phenyl-6-(4-pyridin-2-ylphenyl)hex-4-en-3-one

Part I Potassium tert-butoxide (26.5 g, 1.6 equivalents) intetrahydrofuran (250 mL) under N₂ at about −17° C. was treated with2-(p-tolyl)pyridine (25 g, 1 equivalent), stirred at −17° C. for about10 minutes, and treated dropwise with of n-butyl lithium (2.5 M inhexane, 94.5 mL 1.6 equivalent), maintaining the internal temperature atabout <−13° C. After the addition was completed, the reaction mixturewas warmed up to room temperature and stirred for 1 hr.

Part II A solution of commercially available4S-4-dibenzylamino-3-oxo-5-phenyl-pentanenitrile (50 g, 0.92 equivalent)in tetrahydrofuran (250 mL) was cooled to about 2° C., treated withtert-butyl magnesium chloride (143 mL), stirred at about 2° C. for 30min, treated with the solution from Part I at about 2° C. and stirred atabout 25° C. overnight. The reaction mixture was quenched with saturatedNH₄Cl solution at 5° C. and diluted with 250 mL of ethyl acetate. Theisolated organic layer was washed with aqueous NH₄Cl and brine. Assayyield: 57.4 g. Yield: 78.7%. The isolated organic layer was concentratedto yield the crude title compound.

EXAMPLE 2-2(2S,3S,5S)-5-amino-2-(dibenzylamino)-1-phenyl-6-(4-pyridin-2-ylphenyl)hexan-3-ol

To a jacketed round bottom 1L flask was added 27.5 g (1 eq) of theproduct of Example 2-1, 300 mL of dimethylacetamide and 30 mL ofisopropyl alcohol. The reaction solution was cooled to about −16° C. andtreated with 33 mL (10 eq) of methanesulfonic acid slowly (The reactionwas exothermal, temperature raised to 9° C.). The mixture was cooled toabout −16° C., treated with 54.1 g (5 equivalents) of sodiumtriacetoxylborohydride. Mixed at −16° C. for about 2 hrs and 30 min,HPLC showed the first reduction was completed. 67.9 mL (10 equivalents)of triethanolamine was then added slowly (exothermal). The mixture wasstirred at about −16° C. for 1 hr. 7.7 g of sodium borohydride was addedin 7 portions. The reaction mixture was stirred at −16° C. until thereduction was completed as indicated by HPLC (Column: YMC QDS-AQ 15 cm,flow 1 ml/1 min, Gradient system: 0-15 min, 80% 0.03M HK₂PO₄/20%CH₃CN/to 20% 0.03M HK₂PO₄/80% CH₃CN, 15-20 hold at 20% 0.03M HK₂PO₄/80%CH₃CN, 20-21 min, 20% 0.03M HK₂PO₄/80% CH₃CN to 80% 0.03M HK₂PO₄/20%CH₃CN, 21-23 min, hold at 80% 0.03M HK₂PO₄/20% CH₃CN), treated with 100mL of water, stirred at room temperature overnight and diluted with 300mL of dichloromethane to the reaction mixture. The isolateddichloromethane layer (Assay: 23 g, yield: 83.5%. ds: 95% as measured byHPLC (Column: YMC QDS-AQ 15 cm, flow 1 ml/1 min, Gradient system: 0-15min, 80% 0.03M HK₂PO₄/20% CH₃CN/ to 20% 0.03M HK₂PO₄/80% CH₃CN, 15-20hold at 20% 0.03M HK₂PO₄/80% CH₃CN, 20-21 min, 20% 0.03M HK₂PO₄/80%CH₃CN to 80% 0.03M HK₂PO₄/20% CH₃CN, 21-23 min, hold at 80% 0.03MHK₂PO₄/20% CH₃CN) was extracted with 0.3% H₃PO₄ solution (3×200 mL). ThepH of the isolated aqueous layer was adjusted to 6-7 with sodiumcarbonate. The resulting solution was extracted with dichloromethane(2×300 ml). The combined isolated dichloromethane layers were washedwith 200 mL of 5% aqueous KH₂PO₄, dried (Na₂SO₄) and concentrated. Theresulting residue was dissolved in 100 mL of isopropyl acetate andwashed sequentially with 100 mL of 5% KH₂PO₄ and brine. The isopropylacetate solution was concentrated and 21.2 g of the title compound wasobtained as a yellow foam.

EXAMPLE 2-3(2S,3S,5S)-2,5-diamino-1-phenyl-6-(4-pyridin-2-ylphenyl)hexan-3-ol

A solution of the product of Example 2-2 (3.8 g) in methanol (65 mL) ina three-necked round bottom flask equipped with a condenser was flushedwith nitrogen, treated with water (5 mL), ammonium formate (2.5 g) andPd/C (1.0 g), and stirred under nitrogen at 60° C. for 12 hours. Thereaction mixture was cooled, filtered, and concentrated. A solution ofthe residue in dichloromethane (100 mL) was washed with saturatedaqueous NaHCO₃ (3×50 mL). The isolated dichlormethane layer wasconcentrated to afford 3.3 g of the crude product.

EXAMPLE 2-4methyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate

A mixture of (2S)-2-[(methoxycarbonyl)amino]-3,3-dimethyl-butanoic acid(2.6 g, 2.05 equivalents),O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate(5.1 g, 2.05 eq), diisopropylethylamine (6.9 mL, 6 equivalents) in ethylacetate (30 mL) and acetonitrile (3 mL) was stirred at room temperaturefor 2 hrs until the suspension turned to a clear solution, treated witha solution of the product of Example 2-3 (3.3 g) in ethyl acetate (10mL), stirred at room temperature overnight, and filtered. The isolatedwhite solid was dissolved in acetonitrile (45 mL) at 75° C. After mixingat 75° C. for 1 hr, the solution was cooled down to room temperature andstirred for 2 hrs and filtered. The isolated solid was washed withacetonitrile (30 mL) and dried to afford the title compound as a whitesolid. Potency: 96%. Yield over two steps: 70%. ¹H NMR (DMSO-d₆) δ ppm0.79 (s, 9H), 0.81(s, 9H),1.52(m, 2H), 2.51 (m, 1H), 2.72 (m, 3H), 3.48(s, 3H), 3.54 (s, 3H), 3.63 (m, 1H), 3.81 (d, J=8 Hz, 1H), 3.89 (d, J=8Hz, 1H), 4.00-4.20 (m, 2H), 4.85 (d, J=8 Hz, 1H), 6.58 (d, J=8 Hz, 1H),6.76 (d, J=8 Hz, 1H), 7.107.18 (m, 7H), 7.30 (m, 1H), 7.53 (m, 1H),7.81-7.87 (m, 5H), 8.608.62 (d, J=8Hz, 1H).

EXAMPLE 3methyl(1S)-1-{[((1S,3S,4S)-1-benzyl-3-hydroxy-4-{[(2S)-3-methyl-2-(2-oxo-3-{[2-(2-pyridinyl)-1,3-thiazol-4-yl]methyl}-1-imidazolidinyl)pentanoyl]amino}-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamateEXAMPLE 3A9H-fluoren-9-ylmethyl(1S,2S,4S)-1-benzyl-2-hydroxy-4-[(tert-butoxycarbonyl)amino]-5-phenylpentylcarbamate

A solution of the product of Example 126 (1.0 g, 2.0 mmol) in a mixtureof dioxane (15 mL) and water (5 mL) was treated with sodium bicarbonate(0.37 g, 4.4 mmol) and N-(9-fluorenylmethyloxycarbonyloxy)-succinimide(0.74 g, 2.2 mmol), stirred at 25° C. for 16 hours and partitionedbetween ethyl acetate and diluted sodium bicarbonate solution. Theorganic phase was washed with brine and dried over MgSO₄, filtered andconcentrated to give the title compound (1.37 g), which was used withoutfurther purification.

EXAMPLE 3B9H-fluoren-9-ylmethyl(1S,2S,4S)-4-amino-1-benzyl-2-hydroxy-5-phenylpentylcarbamate

A solution containing the product of Example 3A (0.92 g, 1.5 mmol) indioxane (5 mL) was treated with HCl solution (15 mL, 4 N in dioxane) at0° C., stirred at 25° C. for 1 hour and concentrated. The residue wastriturated with hexanes to give the title compound as the hydrochloridesalt (0.82 g).

EXAMPLE 3Cmethyl(1S)-1-{[((1S,3S,4S)-1-benzyl-4-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-3-hydroxy-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamate

A solution of the product of Example 3B (0.150 g, 0.276 mmol) in DMF (3mL) was treated with the product of Example 1F (0.052 g, 0.275 mmol),EDAC (0.080 g, 0.417 mmol), HOBT (0.055, 0.407 mmol), and NMM (0.090 mL,0.819 mmol) at 0° C., stirred at 25° C. for 2 hours, and partitionedbetween ethyl acetate and water. The organic phase was washed with 10%citric acid, diluted sodium bicarbonate, and brine, dried over MgSO₄,filtered and concentrated. The concentrate was purified by reversedphase chromatography on a C18 column, eluting with a gradient startingwith 5%-100% acetonitrile in water (0.1% TFA) to give the title compound(0.130 g, 70% yield).

EXAMPLE 3Dmethyl(1S)-1-({[(1S,3S,4S)-4-amino-1-benzyl-3-hydroxy-5-phenylpentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate

A solution of the product of Example 3C (0.130 g, 0.192 mmol) in DMF (6mL) was treated with diethylamine (1.5 mL), stirred at 25° C. for 1hour, and partitioned between ethyl acetate and water. The organic phasewas washed with brine, dried over MgSO₄, filtered and concentrated. Theresidue was chromatographed on silica gel eluting with a gradientstarting with ethyl acetate and ending with methanol to give the titlecompound (0.52 g, 60% yield).

EXAMPLE 3E (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetaldehyde

A solution of phthalimidoacetaldehyde diethyl acetal (39.6 g, 150.4mmol) in a mixture of THF (80 mL) and aqueous HCl (50 mL, 10%) washeated at 75° C. for 5 hours, cooled to 25° C. and partitioned betweenethyl acetate and half-saturated NaHCO₃. The organic phase was washedwith brine, dried over MgSO₄, filtered and concentrated to give thetitle compound (36.81 g), which was used without further purification.

EXAMPLE 3Ftert-butyl(2S,3S)-2-{[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]amino}-3-methylpentanoate

A solution of the product of Example 3E (36.81 g) in methanol (50 mL)was treated with L-iso-leucine tert-butyl ester hydrochloride (30 g, 134mmol), sodium cyanoborohydride (16.9 g, 268 mmol), and acetic acid (4.6ml, 80.4 mmol), stirred at 25° C. for 3 hours and concentrated. Theconcentrate was partitioned between dichloromethane and saturatedNaHCO₃. The organic phase was washed with brine and dried over MgSO₄,filtered and concentrated. The residue was chromatographed on silicagel, eluting with a gradient starting with 10%-66% ethyl acetate inhexanes to give the title compound (28.44 g, 59% yield).

EXAMPLE 3G tert-butyl(2S,3S)-2-[(2-aminoethyl)amino]-3-methylpentanoate

A solution of the product of Example 3F (28.44 g, 78.9 mmol) in ethanol(400 mL) was treated with hydrazine hydrate (25 mL, 789 mmol), stirredat 70° C. for 2 hours, cooled to 25° C. The solid precipitate wasdissolved by addition of aqueous NaOH solution (200 mL, 1 N). Thereaction was partitioned between dichloromethane and water. The aqueouswas extracted three times with dichloromethane. The combined organicextracts were dried over MgSO₄, filtered and concentrated to give thetitle compound (15.4 g, 85% yield), which was used without furtherpurification.

EXAMPLE 3H 2-pyridinecarbothioamide

A solution of pyridine-2-carboxamide (3.1 g, 25.4 mmol) in toluene (25mL) was treated with Laweson's reagent (5.1 g, 12.6 mmol), heated at 85°C. for 64 hours, cooled to 25° C., and partitioned between ethyl acetateand water. The organic phase was washed with brine, dried over MgSO₄,filtered and concentrated to give the title compound, which was usedwithout further purification.

EXAMPLE 3I ethyl 2-(2-pyridinyl)-1,3-thiazole-4-carboxylate

A solution of the product of Example 3H (25.4 mmol) in ethanol (50 mL)was treated with ethyl bromopyruvate (3 mL, 23.9 mmol) and molecularsieves (10 g, 3 Å), heated at reflux for 16 hours, cooled to 25° C.,filtered and concentrated. The concentrate was partitioned between ethylacetate and saturated NaHCO₃, and the organic phase was washed withbrine, dried over MgSO₄, filtered and concentrated. The residue waschromatographed on silica gel eluting with 0-25% ethyl acetate indichloromethane to give the title compound (1.98 g, 33% yield).

EXAMPLE 3J 2-(2-pyridinyl)-1,3-thiazole-4-carbaldehyde

A solution containing the product of Example 31 (0.91 g, 3.9 mmol) indichloromethane (13 mL) was treated dropwise with DIBAL (7.4 mL, 1 M indichloromethane) at −78° C., stirred at −78° C. for 1 hour, treated withacetic acid (0.8 mL) and warmed to 25° C. A 10% solution of aqueoussodium potassium tartrate was added and the mixture was stirredvigorously for 1 hour. The reaction mixture was partitioned betweenchloroform and water, and the organic phase was washed with brine, driedover MgSO₄, filtered and concentrated. The residue was chromatographedon silica gel eluting with 0-10% ethyl acetate in dichloromethane togive the title compound (0.39 g, 53% yield).

EXAMPLE 3Ktert-butyl(2S,3S)-3-methyl-2-(2-oxo-3-{[2-(2-pyridinyl)-1,3-thiazol-4-yl]methyl}-1-imidazolidinyl)pentanoate

A solution containing the product of Example 3G (0.30 g, 1.30 mmol) in amixture of benzene (3 mL) and ethanol (3 mL) was treated with theproduct of Example 3J (0.25 g, 1.31 mmol), heated at 70° C. for 16hours, cooled to 25° C., treated with sodium borohydride (0.15 g, 3.97mmol), stirred at 25° C. for 3 hours, quenched with sodium bicarbonatesolution and partitioned between ethyl acetate and water. The organicphase was washed with brine, dried over MgSO₄, filtered andconcentrated. A solution of the residue (1.3 mmol) in 1,2-dichloroethane(50 mL) was treated with bis(4-nitrophenyl) carbonate (0.425 g, 1.40mmol) and triethylamine (0.225 ml, 1.83 mmol), heated at 70° C. for 16hours, and partitioned between ethyl acetate and saturated NaHCO₃. Theorganic phase was washed with brine, dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with0-35% ethyl acetate in dichloromethane to give the title compound (0.214g, 38% yield).

EXAMPLE 3L(2S,3S)-3-methyl-2-(2-oxo-3-{[2-(2-pyridinyl)-1,3-thiazol-4-yl]methyl}-1-imidazolidinyl)pentanoicacid trifluoroacetate

A solution containing the product of Example 3K (0.214 g, 0.50 mmol) indichloromethane (2 mL) was treated with trifluoracetic acid (2 mL),stirred at 25° C. for 1 hour and concentrated. The residue waschromatographed on silica gel eluting with 0-15% methanol indichloromethane to give the title compound (0.24 g) as thetrifluoroacetic acid salt.

EXAMPLE 3Mmethyl(1S)-1-{[((1S,3S,4S)-1-benzyl-3-hydroxy4-{[(2S)-3-methyl-2-(2-oxo-3-{[2-(2-pyridinyl)-1,3-thiazol-4-yl]methyl}-1-imidazolidinyl)pentanoyl]amino}-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamate

A solution containing the product from Example 3D (0.025 g, 0.055 mmol)in DMF (0.5 mL) was treated with the product from Example 3L (0.021 g,0.056 mmol), EDAC (0.020 g, 0.104 mmol), HOBT (0.015 g, 0.111 mmol), andNMM (0.020 mL, 0.182 mmol) at 0° C., stirred at 25° C. for 16 hours, andpartitioned between ethyl acetate and water. The organic phase waswashed with 10% citric acid, diluted sodium bicarbonate, and brine,dried over MgSO₄, filtered and concentrated. The residue was purified byreversed phase chromatography on a C18 column, eluting with 5-100%acetonitrile in water (0.1% TFA) to give the title compound (0.028 g,63% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.79 (m, 15 H), 0.95 (m, 1H), 1.29 (m, 1 H), 1.49 (m, 2 H), 1.80 (m, 1 H), 2.68 (m, 4 H), 3.03 (m,1 H), 3.17(m, 2 H), 3.55 (s, 3 H), 3.63 (m, 3 H), 3.94 (d, J=11.03 Hz, 2H), 4.12 (m, 2 H), 4.47 (m, 2 H), 6.62 (d, J=9.93 Hz, 1 H), 7.07 (m, 10H), 7.25 (d, J=9.56 Hz, 1 H), 7.48 (m, 1 H), 7.57 (s, 1 H), 7.75 (d,J=8.46 Hz, 1 H), 7.93 (m, 1 H), 8.10 (d, J=8.09 Hz, 1 H), 8.62 (d,J=4.04 Hz, 1 H).

EXAMPLE 4methyl(1S)-1-({[(1S,3S,4S)-1-benzyl-3-hydroxy-4-({(2S)-3-methyl-2-[2-[oxo-3-(4-quinolinylmethyl)-1-imidazolidinyl]pentanoyl}amino)-5-phenylpentyl]amino}carbonyl)-2,2-dimethylpropylcarbamateEXAMPLE 4A(2S,3S)-3-methyl-2-[2-oxo-3-(4-quinolinylmethyl)-1-imidazolidinyl]pentanoicacid trifluoroacetate

A solution containing the product from Example 3G (2.0 g, 8.69 mmol) ina mixture of benzene (40 mL) and ethanol (40 mL) was treated with4-quinolinecarboxaldehyde (1.4 g, 8.91 mmol), heated at 70° C. for 2hours, cooled to 25° C., treated with sodium borohydride (1.0 g, 26.75mmol), stirred at 25° C. for 16 hours, quenched with sodium bicarbonatesolution and partitioned between ethyl acetate and water. The organicphase was washed with brine, dried over MgSO₄, filtered andconcentrated. A solution of the residue (8.69 mmol) in1,2-dichloroethane (300 mL) was treated with bis(4-nitrophenyl)carbonate (3.0 g, 9.86 mmol), heated at 70° C. for 16 hours, andpartitioned between ethyl acetate and saturated NaHCO₃. The organicphase was washed with brine, dried over MgSO₄, filtered andconcentrated. A solution of the residue (8.69 mmol) in dichloromethane(40 mL) was treated with trifluoracetic acid (40 mL), stirred at 25° C.for 1 hour and concentrated. The residue was chromatographed on silicagel eluting with 0-5% methanol in dichloromethane. A second purificationusing reversed phase chromatography on a C18 column, eluting with 5-100%acetonitrile in water (0.1% TFA) afforded the title compound (1.91 g,48% yield).

EXAMPLE 4Bmethyl(1S)-1-({[(1S,3S,4S)-1-benzyl-3-hydroxy-4-({(2S)-3-methyl-2-[2-oxo-3-(4-quinolinylmethyl)-1-imidazolidinyl]pentanoyl}amino)-5-phenylpentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate

A solution containing the product from Example 3D (0.078 g, 0.171 mmol)in DMF (0.5 mL) was treated with the product from Example 4A (0.070 g,0.205 mmol), EDAC (0.050 g, 0.261 mmol), HOBT (0.035 g, 0.259 mmol), andNMM (0.060 mL, 0.546 mmol) at 0° C., stirred at 25° C. for 16 hours andpartitioned between ethyl acetate and water. The organic phase waswashed with 10% citric acid, diluted sodium bicarbonate, and brine,dried over MgSO₄, filtered and concentrated. The residue was purified byreversed phase chromatography on a C18 column, eluting with 5-100%acetonitrile in water (0.1% TFA) to give the title compound (0.030 g,23% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.79 (m, 15 H), 1.00 (m, 1H), 1.25 (m, 1 H), 1.51 (m, 2 H), 1.82 (m, 1 H), 2.64 (m, 5 H), 3.02 (m,3 H), 3.55 (s, 3 H), 3.63 (m, 1 H), 3.82 (d, J=9.93 Hz, 1 H), 3.99 (d,J=11.03 Hz, 1 H), 4.13 (m, 2 H), 4.64 (d, J=7.72 Hz, 1 H), 4.80 (m, 2H), 6.62 (d, J=9.93 Hz, 1 H), 6.98 (m, 5 H), 7.14 (m, 5 H), 7.32 (d,J=9.56 Hz, 1 H), 7.41 (d, J=4.41 Hz, 1 H), 7.62 (t, J=7.54 Hz, 1 H),7.76 (m, 2 H), 8.06 (d, J=7.72 Hz, 1 H), 8.30 (d, J=8.46 Hz, 1 H), 8.88(d, J=4.41 Hz, 1 H).

EXAMPLE 5methyl(1S)-1-({[(1S,3S,4S)-1-benzyl-3-hydroxy-4-({(2S)-3-methyl-2-[2-oxo-3-(4-quinolinylmethyl)-1-imidazolidinyl]pentanoyl}amino)-5-phenylpentyl]amino}carbonyl)-2-methylbutylcarbamateEXAMPLE 5A (2S,3S)-2-[(methoxycarbonyl)amino]-3-methylpentanoic acid

A solution of L-iso-Leucine (7.43 g, 56.6 mmol) in a mixture of dioxane(28 mL) and aqueous NaOH solution (93.5 mL, 2N) was treated with methylchloroformate (8.75 mL, 113.3 mmol) dropwise, not allowing the internaltemperature to rise above 50° C. The mixture was warmed to 60° C. andstirred for 18 hours, cooled to 25° C., and extracted withdichloromethane. The aqueous phase was cooled to 0° C., and its pH wasadjusted to 1-2 with HCl (4 N). The mixture was partitioned betweenethyl acetate and water, and the organic phase was washed with brine,dried over Na₂SO₄, filtered and concentrated to give the crude product(10 g).

EXAMPLE 5Bmethyl(1S,2S)-1-{[((1S,3S,4S)-1-benzyl-4-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-3-hydroxy-5-phenylpentyl)amino]carbonyl}-2-methylbutylcarbamate

A solution containing the product from Example 3B (0.150 g, 0.276 mmol)in DMF (3 mL) was treated with the product from Example 5A (0.063 g,0.333 mmol), EDAC (0.080 g, 0.417 mmol), HOBT (0.055, 0.407 mmol), andNMM (0.090 mL, 0.819 mmol) at 0° C., stirred at 25° C. for 16 hours, andpartitioned between ethyl acetate and water. The organic phase waswashed with 10% citric acid, dilute sodium bicarbonate solution, andbrine, dried over MgSO₄, filtered and concentrated. The concentrate waspurified by reversed phase chromatography on a C18 column, eluting with5%-100% acetonitrile in water (0.1% TFA) to give the title compound(0.107 g, 57% yield).

EXAMPLE 5Cmethyl(1S,2S)-1-({[(1S,3S,4S)-4-amino-1-benzyl-3-hydroxy-5-phenylpentyl]amino}carbonyl)-2-methylbutylcarbamate

A solution containing the product from Example 5B (0.107 g, 0.158 mmol)in DMF (6 mL) was treated with diethylamine (1.5 mL), stirred at 25° C.for 1 hour, and partitioned between ethyl acetate and water. The organicphase was washed with brine, dried over MgSO₄, filtered and concentratedto give the title compound, which was used without further purification.

EXAMPLE 5Dmethyl(1S)-1-({[(1S,3S,4S)-1-benzyl-3-hydroxy-4-({(2S)-3-methyl-2-[2-oxo-3-(4-quinolinylmethyl)-1-imidazolidinyl]pentanoyl}amino)-5-phenylpentyl]amino}carbonyl)-2-methylbutylcarbamate

A solution containing the product from Example 5C (0.078 g, 0.171 mmol)in DMF (0.5 mL) was treated with the product from Example 4A (0.070 g,0.205 mmol), EDAC (0.050 g, 0.261 mmol), HOBT (0.035 g, 0.259 mmol), andNMM (0.060 mL, 0.546 mmol) at 0° C., stirred at 25° C. for 16 hours, andpartitioned between ethyl acetate and water. The organic phase waswashed with 10% citric acid, diluted sodium bicarbonate, and brine,dried over MgSO₄, filtered and concentrated. The residue was purified byreversed phase chromatography on a C18 column eluting with 5-100%acetonitrile in water (0.1% TFA) to give the title compound (0.030 g,23% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.76 (m, 12 H), 1.00 (m, 2H), 1.29 (m, 2 H), 1.49 (m, 3 H), 1.81 (m, 1 H), 2.65 (m, 5 H), 3.01 (m,3 H), 3.54 (s, 3 H), 3.61 (m, 1 H), 3.75 (t, J=8.82 Hz, 1 H), 3.99 (d,J=11.03 Hz, 1 H), 4.13 (m, 2 H), 4.62 (d, J=7.35 Hz, 1 H), 4.80 (m, 2H), 6.89 (d, J=9.56 Hz, 1 H), 6.98 (m, 5 H), 7.15 (m, 5 H), 7.32 (d,J=9.93 Hz, 1 H), 7.41 (d, J=4.41 Hz, 1 H), 7.66 (m, 2 H), 7.77 (t,J=6.99 Hz, 1 H), 8.06 (d, J=7.72 Hz, 1 H), 8.30 (d, J=8.09 Hz, 1 H),8.88 (d, J=4.41 Hz, 1 H).

EXAMPLE 6methyl(1S)-1-{[((1S,3S,4S)-1-benzyl-3-hydroxy-4-{[(2S)-2-(3-{[2-(methoxymethyl)-1,3-thiazol-4-yl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamateEXAMPLE 6Atert-butyl(1S,3S,4S)-4-amino-1-benzyl-3-hydroxy-5-phenylpentylcarbamate

The product from Example 126 (20 g, 39.8 mmol) was partitioned betweenethyl acetate and saturated NaHCO₃ solution with stirring for 30minutes. The solid white amine was collected by filtration and theaqueous was extracted twice with portions of ethyl acetate. The solidmaterial collected was dissolved in warm ethyl acetate and this solutionwas combined with the organic phase extracts, dried over sodium sulfate,filtered and concentrated to give the free amine (14.15 g).

EXAMPLE 6B 2-methoxyethanethioamide

A solution containing methoxyacetyl chloride (10 g, 92.15 mmol) andammonium acetate (7.1 g, 92.11 mmol) in acetone (250 mL) was stirred at25° C. for 16 hours, treated with phosphorous pentasulfide (4.1 g, 9.22mmol), stirred at 25° C. for 64 hours, concentrated and partitionedbetween ethyl acetate and water. The organic phase was washed withbrine, dried over MgSO₄, filtered and concentrated to give the titlecompound (7.0 g, 72% yield), which was used without furtherpurification.

EXAMPLE 6C ethyl 2-(methoxymethyl)-1,3-thiazole-4-carboxylate

A solution containing the product from Example 6B (7 g, 66.6 mmol) inacetone (270 mL) was treated with ethyl bromopyruvate (8.4 mL, 66.6mmol) and magnesium sulfate (7.9 g, 66.6 mmol), heated at reflux for 16hours, cooled to 25° C., filtered and concentrated. The residue waschromatographed on silica gel eluting with chloroform to give the titlecompound (7.6 g, 57% yield).

EXAMPLE 6D 2-(methoxymethyl)-1,3-thiazole-4-carbaldehyde

A solution containing the product from Example 6C (7.4 g, 36.8 mmol) indichloromethane (40 mL) was treated with DIBAL (73.6 mL, 1 M indichloromethane) dropwise at −78° C. over 2 hours, stirred at −78° C.for 2 hours, treated with acetic acid (10 mL) at −78° C. and warmed to25° C. A 10% solution of aqueous sodium potassium tartrate was added andthe mixture was stirred vigorously for 1 hour. The reaction mixture waspartitioned between chloroform and water. The organic phase was washedwith brine, dried over MgSO₄, filtered and concentrated. The residue waschromatographed on silica gel eluting with 0-100% ethylacetate/dichloromethane to give the title compound (5.78 g, 71% yield).

EXAMPLE 6E tert-butyl(2S)-2-{[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]amino}-3,3-dimethylbutanoate

A solution of the product of Example 3E (9.34 g, 49.4 mmol) in methanol(33 mL) was treated with L-tert-leucine tert-butyl ester hydrochloride(10 g, 44.9 mmol), sodium cyanoborohydride (5.6 g, 89.8 mmol), andacetic acid (1.5 ml, 26.2 mmol), stirred at 25° C. for 4 hours, andpartitioned between chloroform and saturated NaHCO₃. The organic phasewas washed with brine, dried over MgSO₄, filtered and concentrated. Theresidue was chromatographed on silica gel, eluting with first with 66%chloroform in hexanes and then with 33% ethyl acetate in chloroform togive the title compound (10.5 g, 59% yield).

EXAMPLE 6F tert-butyl (2S)-2-[(2-aminoethyl)amino]-3,3-dimethylbutanoate

A solution of the product from Example 6E (10.5 g, 29.1 mmol) in ethanol(290 mL) was treated with hydrazine hydrate (9 mL, 290 mmol), heated at70° C. for 2 hours and cooled to 25° C. The solid precipitate wasdissolved by addition of aqueous NaOH solution (150 mL, 1 N). Thereaction mixture was partitioned between chloroform and water, and theaqueous was extracted three times with chloroform. The combined organicextracts were dried over MgSO₄, filtered and concentrated to give thediamine (7.0 g, quantitative), which was used without furtherpurification.

EXAMPLE 6Gtert-butyl(2S)-2-(3-{[2-(methoxymethyl)-1,3-thiazol-4-yl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoate

A solution containing the product from Example 6F (1.0 g, 4.34 mmol) ina mixture of benzene (12 mL) and ethanol (12 mL) was treated with theproduct from Example 6D (0.682 g, 4.34 mmol), heated at 50° C. for 1.5hours, cooled to 25° C., treated with sodium borohydride (0.329 g, 8.68mmol), stirred at 25° C. for 1.5 hours, quenched with sodium bicarbonatesolution, and partitioned between ethyl acetate and water. The organicphase was washed with brine, dried over MgSO₄, filtered andconcentrated. A solution of the residue (4.34 mmol) in toluene (25 mL)was treated with bis(4-nitrophenyl) carbonate (1.58 g, 5.21 mmol),heated at 60° C. for 16 hours, and partitioned between ethyl acetate andsaturated NaHCO₃. The organic phase was washed with brine, dried overMgSO₄, filtered and concentrated to give the title compound (1.28 g, 74%yield), which was used without further purification.

EXAMPLE 6H(2S)-2-(3-{[2-(methoxymethyl)-1,3-thiazol-4-yl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoicacid trifluoroacetate

A solution containing the product from Example 6G (1.28 g, 3.2 mmol) indichloromethane (10 mL) was treated with trifluoracetic acid (5 mL),stirred at 25° C. for 4 hours and concentrated. The residue waschromatographed on silica gel eluting with 0-5% methanol indichloromethane to give the title compound (1.2 g) as thetrifluoroacetic acid salt.

EXAMPLE 6Itert-butyl(1S,3S,4S)-1-benzyl-3-hydroxy-4-{[(2S)-2-(3-{[2-(methoxymethyl)-1,3-thiazol-4-yl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-5-phenylpentylcarbamate

A solution of the product from Example 6A (0.034 g, 0.089 mmol) in THF(0.9 mL) was treated with the product from Example 6H (0.035 g, 0.103mmol), DEPBT (0.040 g, 0.134 mmol), and N,N-diisopropylethylamine (0.075mL, 0.431 mmol), stirred at 25° C. for 16 hours, and partitioned betweenethyl acetate and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was purified by reversed phase chromatographyusing C18 column, eluting with 5-100% acetonitrile in water (0.1% TFA)to give the title compound (0.047 g, 75% yield).

EXAMPLE 6Jmethyl(1S)-1-{[((1S,3S,4S)-1-benzyl-3-hydroxy-4-{[(2S)-2-(3-{[2-(methoxymethyl)-1,3-thiazol-4-yl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamate

A solution containing the product from Example 61 (0.047 g, 0.066 mmol)in dichloromethane (1 mL) was treated with trifluoroacetic acid (1 mL),stirred at 25° C. for 1 hour, concentrated, and partitioned betweenethyl acetate and saturated NaHCO₃. The organic phase was washed withbrine and dried over MgSO₄, filtered and concentrated. A solution of theresidue (0.030 g, 0.049 mmol) in DMF (0.5 mL) was treated with theproduct from Example 1F (0.010 g, 0.053 mmol), EDAC (0.020 g, 0.104mmol), HOBT (0.015 g, 0.111 mmol), and NMM (0.016 mL, 0.146 mmol) at 0°C., stirred at 25° C. for 16 hours, and partitioned between ethylacetate and water. The organic phase was washed with 10% citric acid,diluted sodium bicarbonate, and brine, and dried over MgSO₄, filteredand concentrated. The residue was purified by reversed phasechromatography on a C18 column, eluting with 5-100% acetonitrile inwater (0.1% TFA) to give the title compound (0.031 g, 79% yield). ¹H NMR(300 MHz, DMSO-d₆), δ ppm 0.82 (s, 9 H), 0.89 (s, 9 H), 1.25 (m, 1 H),1.50 (m, 2 H), 2.37 (m, 1H), 2.65 (d, J=7.35 Hz, 2 H), 2.73 (d, J=9.56Hz, 1 H), 3.02 (m, 2 H), 3.19 (m, 1 H), 3.38 (s, 3 H), 3.55 (s, 3 H),3.85 (m, 3 H), 4.08 (m, 3 H), 4.38 (m, 2 H), 4.68 (s, 2 H), 6.61 (d,J=9.93 Hz, 1 H), 7.08 (m, 10 H), 7.43 (m, 2 H), 7.74 (d, J=8.46 Hz, 1H).

EXAMPLE 7methyl(1S)-1-[({(1S,3S,4S)-1-benzyl-3-hydroxy-4-[((2S)-3-methyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 7Atert-butyl(2S,3S)-3-methyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}pentanoate

A solution containing the product from Example 3G (6.18 g, 26.9 mmol) indichloromethane (160 mL) was treated with6-methyl-2-pyridinecarboxaldehyde (3.25 g, 26.8 mmol) and magnesiumsulfate (16.3 g, 135.4 mmol) g), stirred at 25° C. for 18 hours,filtered and concentrated. A solution of the residue in methanol (160mL) was treated with sodium borohydride (1.2 g, 31.7 mmol), stirred at25° C. for 1 hour, quenched with water, stirred for 15 minutes, andfollowed by evaporation of the solvent. The concentrate was partitionedbetween ethyl acetate and saturated NaHCO₃, and the organic phase waswashed with brine and dried over MgSO₄, filtered and concentrated. Asolution of the residue (9.1 g, 26.8 mmol) in 1,2-dichloroethane (550mL) was treated with N,N-disuccinimidyl carbonate (8.24 g, 32.2 mmol)and triethylamine (3.7 mL, 26.5 mmol), stirred at 25° C. for 68 hours,partitioned with 10% Na₂CO₃, and the organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with0-100% ethyl acetate/dichloroform to give the title compound (6.15 g,63% yield).

EXAMPLE 7B(2S,3S)-3-methyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}pentanoicacid

A solution containing the product from Example 7A (6.15 g, 17.0 mmol) indichloromethane (150 mL) was treated with trifluoracetic acid (50 mL),stirred at 25° C. for 2 hours and concentrated. The residue was purifiedby reversed phase chromatography on a C18 column, eluting with 5-100%acetonitrile in water (0.1% TFA) to give the title compound (6.0 g, 84%yield) as the trifluoroacetic acid salt.

EXAMPLE 7Ctert-butyl(1S,3S,4S)-1-benzyl-3-hydroxy-4-[((2S,3S)-3-methyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenylpentylcarbamate

A solution of the product from Example 6A (0.046 g, 0.119 mmol) in THF(0.9 mL) was treated with the product from Example 7B (0.050 g, 0.119mmol), EDAC (0.035 g, 0.183 mmol), HOBT (0.025 g, 0.185 mmol), and NMM(0.040 mL, 0.364 mmol) at 0° C., stirred at 25° C. for 16 hours, andpartitioned between ethyl acetate and water. The organic phase waswashed with 10% citric acid, dilute sodium bicarbonate solution, andbrine, dried over MgSO₄, filtered and concentrated. The residue waspurified by reversed phase chromatography on a C18 column, eluting with5-100% acetonitrile in water (0.1% TFA) to give the title compound(0.080 g, 100% yield).

EXAMPLE 7Dmethyl(1S)-1-[({(1S,3S,4S)-1-benzyl-3-hydroxy-4-[((2S)-3-methyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 7C (0.080 g, 0.119 mmol)in dichloromethane (1 mL) was treated with trifluoroacetic acid (1 mL),stirred at 25° C. for 1 hour and concentrated. The concentrate waspartitioned between ethyl acetate and saturated NaHCO₃. The organicphase was washed with brine, dried over MgSO₄, filtered andconcentrated. A solution of the residue (0.056 g, 0.098 mmol) in DMF (1mL) was treated with the product from Example 1F (0.020 g, 0.106 mmol),EDAC (0.030 g, 0.156 mmol), HOBT (0.020 g, 0.148 mmol), and NMM (0.030mL, 0.273 mmol) at 0° C., stirred at 25° C. for 16 hours, andpartitioned between ethyl acetate and water. The organic phase waswashed with 10% citric acid, dilute sodium bicarbonate, and brine, anddried over MgSO₄, filtered and concentrated. The residue was purified byreversed phase chromatography on a C18 column, eluting with 5-100%acetonitrile in water (0.1% TFA) to give the title compound (0.049 g,67% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.79 (m, 15 H), 0.93 (m, 2H), 1.31 (m, 1 H), 1.50 (m, 2 H), 1.82 (m, 1 H), 2.45 (s, 3 H), 2.67 (m,4 H), 3.06 (m, 3 H), 3.55 (s, 3 H), 3.64 (m, 1 H), 3.82 (d, J=9.93 Hz, 1H), 3.93 (d, J=11.03 Hz, 1 H), 4.13 (m, 2 H), 4.35 (s, 2 H), 4.64 (d,J=7.35 Hz, 1 H), 6.62 (d, J=9.93 Hz, 1 H), 7.02 (d, J=7.72 Hz, 1 H),7.13 (m, 11 H), 7.26 (d, J=9.93 Hz, 1 H), 7.66 (t, J=7.72 Hz, 1 H), 7.75(d, J=8.46 Hz, 1 H).

EXAMPLE 8methyl(1S)-1-[({(1S,2S,4S)-1-benzyl-2-hydroxy-4-[((2S)-3-methyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 8Amethyl(1S)-1-[({(1S,2S,4S)-1-benzyl-4-[(tert-butoxycarbonyl)amino]-2-hydroxy-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution of the product from Example 1F (7.0 g, 37.0 mmol), EDAC (8.5g, 44.3 mmol), HOBT (6.0 g, 44.4 mmol), and NMM (8.0 mL, 72.8 mmol) inDMF (30 mL) was stirred at 25° C. for 1 hour, treated with a solution ofthe product from Example 6A (14.15 g, 36.8 mmol) in DMF (30 mL), stirredat 25° C. for 16 hours, concentrated, and partitioned between ethylacetate and saturated NaHCO₃. The organic phase was washed withsaturated NaHCO₃ and brine, and concentrated. The solution of theresidue in hot methanol (20 mL) and water (10 mL) was allowed to cooland stand for 16 hours. The solids were collected by filtration andrinsed several times with hexanes, followed by drying under vacuum togive the title compound (16.97 g, 77% yield).

EXAMPLE 8Bmethyl(1S)-1-({[(1S,2S,4S)-4-amino-1-benzyl-2-hydroxy-5-phenylpentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate

A solution containing the product from Example 8A (16.97 g, 30.6 mmol)in THF (150 mL) was treated with HCl solution (50 mL, 4 N in dioxane),stirred at 60° C. for 2 hours, cooled and adjusted to pH 8 with 10% NaOHsolution. The reaction mixture was partitioned between ethyl acetate andwater, and the organic phase was washed with brine and concentrated togive the title compound (13.74 g).

EXAMPLE 8Cmethyl(1S)-1-[({(1S,2S,4S)-1-benzyl-2-hydroxy-4-[((2S)-3-methyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 8B (5.67 g, 12.5 mmol) inTHF (124 mL) was treated with the product from Example 7B (3.8 g, 12.5mmol), DEPBT (5.59 g, 18.7 mmol), and N,N-diisopropylethylamine (10.8mL, 62.0 mmol), stirred at 25° C. for 16 hours, and partitioned betweenethyl acetate and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting witha gradient starting with dichloromethane and ending with acetone to givethe title compound (4.42 g, 48% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm0.68 (d, J=6.25 Hz, 3 H), 0.82 (m, 14 H), 0.92 (m, 1 H), 1.30 (m, 1 H),1.50 (m, 2 H), 1.79 (m, 1 H), 2.43 (m, 3 H), 2.68 (m, 3 H), 2.89 (m, 1H), 3.10 (m, 3 H), 3.57 (m, 3 H), 3.89 (m, 2 H), 4.13 (m, 2 H), 4.34 (s,2 H), 4.79 (d, J=5.52 Hz, 1 H), 6.80 (d, J=9.56 Hz, 1 H), 7.11 (m, 12H), 7.50 (d, J=8.82 Hz, 1 H), 7.66 (t, J=7.54 Hz, 1 H), 7.83 (d, J=9.19Hz, 1 H).

EXAMPLE 9methyl(1S)-1-[({(1S,2S,4S)-1-benzyl-2-hydroxy-4-[((2S)-3-methyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenylpentyl}amino)carbonyl]-2-methylbutylcarbamateEXAMPLE 9Amethyl(1S,2S)-1-[({(1S,2S,4S)-1-benzyl-4-[(tert-butoxycarbonyl)amino]-2-hydroxy-5-phenylpentyl}amino)carbonyl]-2-methylbutylcarbamate

A solution of the product from Example 6A (0.50 g, 1.30 mmol) in THF (13mL) was treated with the product from Example 5A (0.30 g, 1.59 mmol),DEPBT (0.45 g, 1.50 mmol), and N,N-diisopropylethylamine (1.1 mL, 6.31mmol), stirred at 25° C. for 16 hours, and partitioned between ethylacetate and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated to give the title compound, used without furtherpurification.

EXAMPLE 9Bmethyl(1S,2S)-1-({[(1S,2S,4S)-4-amino-1-benzyl-2-hydroxy-5-phenylpentyl]amino}carbonyl)-2-methylbutylcarbamate

A solution containing the crude product from Example 9A in THF (150 mL)was treated with an HCl solution (5 mL, 4 N in dioxane), and the mixturewas heated at 60° C. for 2 hours, cooled to 25° C. and concentrated. Theconcentrate was partitioned between ethyl acetate and saturated NaHCO₃.The organic phase was washed with brine, dried over MgSO₄, filtered andconcentrated to give the title compound (0.36 g, 61% yield).

EXAMPLE 9Cmethyl(1S)-1-[({(1S,2S,4S)-1-benzyl-2-hydroxy-4-[((2S)-3-methyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenylpentyl}amino)carbonyl]-2-methylbutylcarbamate

A solution containing the product from Example 9B (0.36 g, 0.79 mmol) inTHF (8 mL) was treated with the product from Example 7B (0.33 g, 0.79mmol), DEPBT (0.355 g, 1.19 mmol), and N,N-diisopropylethylamine (0.70mL, 4.02 mmol), stirred at 25° C. for 16 hours, and partitioned betweenethyl acetate and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with0-50% acetone/dichloromethane to give the title compound (0.264 g, 45%yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.75 (m, 12 H), 0.94 (m, 2 H),1.29 (m, 2 H), 1.46 (m, 2 H), 1.62 (m, 1 H), 1.80 (m, 1 H), 2.43 (m, 4H), 2.68 (m, 3 H), 2.88 (m, 1 H), 3.08 (m, 3 H), 3.56 (m, 4 H), 3.84 (m,2 H), 4.15 (m, 2 H), 4.34 (s, 2 H), 4.84 (d, J=5.88 Hz, 1 H), 7.03 (m, 7H), 7.15 (m, 6 H), 7.39 (d, J=9.19 Hz, 1 H), 7.66 (t, J=7.72 Hz, 1 H),7.83 (d, J=8.82 Hz, 1 H).

EXAMPLE 10methyl(1S)-1-[({(1S,2S,4S)-1-benzyl-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 10Atert-butyl(2S)-3,3-dimethyl-2-[(2-{[(6-methyl-2-pyridinyl)methyl]amino}ethyl)amino]butanoate

A solution containing the product from Example 6F (2.0 g, 8.68 mmol) indichloromethane (40 mL) was treated with6-methyl-2-pyridinecarboxaldehyde (1.04 g, 8.59 mmol) and magnesiumsulfate (6.0 g, 49.85 mmol), stirred at 25° C. for 4 hours, filtered andconcentrated. A solution of the residue in methanol (40 mL) at 0° C. wastreated with sodium borohydride (0.5 g, 13.22 mmol), stirred at 25° C.for 1.5 hours, and concentrated. The concentrate was partitioned betweendichloromethane and water, and the aqueous was extracted three timeswith dichloromethane. The combined organic phase was dried over NaSO₄,filtered and concentrated. The residue was chromatographed on silicagel, eluting with 10% methanol in chloroform, to give the title compound(2.48 g, 85% yield).

EXAMPLE 10Btert-butyl(2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoate

A solution containing the product from Example 10A (1.76 g, 5.25 mmol)in 1,2-dichloroethane (210 mL) was treated with N,N-disuccinimidylcarbonate (1.61 g, 6.28 mmol) and triethylamine (0.75 mL, 5.38 mmol),stirred at 25° C. for 16 hours, and partitioned with 10% Na₂CO₃. Theaqueous phase was extracted with additional dichloromethane. Thecombined organic phase was dried over MgSO₄, filtered and concentrated.The residue was chromatographed on silica gel eluting with 0-25% methyltert-butyl ether/dichloromethane to give the title compound (1.33 g, 70%yield).

EXAMPLE 10C(2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoicacid

A solution containing the product from Example 10B (1.33 g, 3.68 mmol)in dichloromethane (20 mL) was treated with trifluoracetic acid (20 mL),stirred at 25° C. for 2 hours and concentrated. The residue was purifiedby reversed phase chromatography on a C18 column, eluting with 0-100%acetonitrile/water (0.1% TFA) to give the title compound (1.44 g, 94%yield) as the trifluoroacetic acid salt.

EXAMPLE 10D(2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoicacid

A solution containing the product from Example 10B (10 g, 27.7 mmol) indichloromethane (100 ml) at −5° C. was slowly treated with an HClsolution in dioxane (200 mL, 4 N), stirred at 40° C. for 6 hrs, stirredat 25° C. for 16 hours concentrated to give the title compound as ahydrochloride salt (10 g, quantitative).

EXAMPLE 10Emethyl(1S)-1-[({(1S,2S,4S)-1-benzyl-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 8B (1.36 g, 2.99 mmol) inTHF (30 mL) was treated with the product from Example 10D (1.25 g, 2.98mmol), DEPBT (1.34 g, 4.48 mmol), and N,N-diisopropylethylamine (2.6 mL,14.9 mmol), stirred at 25° C. for 16 hours, and partitioned betweenethyl acetate and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with0-100% ethyl acetate/dichloromethane, followed by elution with 5%methanol in ethyl acetate. The material obtained after concentration ofall the desired fractions was re-chromatographed on silica gel elutingwith 0-50% acetone/dichloromethane to give the title compound (1.57 g,71% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.84 (s, 9 H), 0.87 (s, 9H), 1.51 (m, 2 H), 2.41 (m, 5 H), 2.65 (dd, J=13.05, 2.76 Hz, 1 H), 2.72(d, J=7.35 Hz, 2 H), 2.97 (m, 1 H), 3.08 (q, J=8.58 Hz, 1 H), 3.24 (m, 1H), 3.58 (m, 3 H), 3.91 (d, J=9.19 Hz, 1 H), 3.97 (s, 1 H), 4.16 (m, 2H), 4.34 (d, J=2.94 Hz, 2 H), 4.80 (d, J=5.52 Hz, 1 H), 6.81 (d, J=9.56Hz, 1 H), 7.07 (m, 6 H), 7.16 (m, 7 H), 7.50 (d, J=9.19 Hz, 1 H), 7.68(t, J=7.72 Hz, 1 H), 7.89 (d, J=9.19 Hz, 1 H).

EXAMPLE 11methyl(1S)-1-[({(1S,2S,4S)-1-benzyl-2-hydroxy-4-[((2S)-3-methyl-2-{3-[(2-methyl-1,3-thiazol-5-yl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 11Atert-butyl(1S,2S,4S)-4-amino-1-benzyl-2-hydroxy-5-phenylpentylcarbamate

A solution of the product from Example 127 (5 g, 17.6 mmol) in toluene(70 mL) was treated with phenyl boronic acid (2.14 g, 17.6 mmol),stirred at reflux until the theoretical amount of water (0.317 mL) wascollected in a Dean-Stark trap. The reaction mixture was cooled to 25°C. and concentrated to dryness, treated with dichloromethane (70 mL) anddi-tert-butyl-dicarbonate (4.0 mL, 17.6 mmol), stirred at 25° C. for 18hours, treated with sodium hydroxide solution (35 mL, 1 N), and stirredfor 10 minutes. The organic phase was washed with water, dried overNa₂SO₄, filtered and concentrated. The residue was chromatographed onsilica gel, eluting with isopropyl amine in dichloromethane to give thetitle compound (2.23 g, 33% yield).

EXAMPLE 11B 2-methyl-1,3-thiazole-4-carbaldehyde

A solution of ethyl 2-methylthiazole-4-carboxylate (1.00 g, 5.8 mmol) intoluene (18 mL) at −78° C. was treated dropwise with a diisobutylaluminum hydride solution in dichloromethane (11.1 mL, 1 M) over 30minutes, stirred at −78° C. for 4 hours, quenched with acetic acid (0.46mL), warmed to 25° C. and concentrated. The concentrate was treated withdichloromethane and Rochelle's salt, stirred vigorously until a clear,two-phase solution formed (approximately 10 minutes). The layers wereseparated and organic layer was washed with 10% NaHCO₃, brine, driedover Na₂SO₄, filtered and concentrated. The residue was chromatographedon silica gel, eluting with 14% ethyl acetate in hexanes to give thetitle compound (0.28 g, 38% yield).

EXAMPLE 11Ctert-butyl(2S,3S)-3-methyl-2-{3-[(2-methyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}pentanoate

A solution containing the product from Example 3G (1.81 g, 7.9 mmol) ina mixture of benzene (8 mL) and methanol (8 mL) was treated with theproduct from Example 11B (1.0 g, 7.9 mmol), stirred at 50° C. for 1hour, cooled to 25° C. and treated with sodium borohydride (0.60 g, 15.7mmol), stirred at 25° C. for 1 hour, quenched with sodium bicarbonatesolution and partitioned between ethyl acetate and water. The organicphase was washed with brine, dried over Na₂SO₄, filtered andconcentrated. A solution of the residue (7.9 mmol) in toluene (16 mL)was treated with bis(4-nitrophenyl) carbonate (2.87 g, 9.4 mmol),stirred at reflux for 16 hours, cooled to 25° C. and partitioned betweenethyl acetate and 10% K₂CO₃. The organic phase was washed with brine,dried over Na₂SO₄, filtered and concentrated. The residue waschromatographed on silica gel eluting with 1% methanol in chloroform togive the title compound (2.0 g, 69% yield).

EXAMPLE 11D(2S,3S)-3-methyl-2-{3-[(2-methyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}pentanoicacid

A solution containing the product from Example 11C (2.0 g, 5.4 mmol) indichloromethane (14 mL) was treated with trifluoracetic acid (7 mL),stirred at 25° C. for 3 hours and concentrated to give the titlecompound as a trifluoroacetic acid salt.

EXAMPLE 11Etert-butyl(1S,2S,4S)-1-benzyl-2-hydroxy-4-[((2S,3S)-3-methyl-2-{3-[(2-methyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenylpentylcarbamate

A solution containing the product from Example 11A (0.42 g, 1.09 mmol)in THF (5 mL) was treated with the product from Example 11D (0.34 g,1.09 mmol), DEPBT (0.65 g, 2.2 mmol), and N,N-diisopropylethylamine(0.57 mL, 3.3 mmol), stirred at 25° C. for 4 hours and partitionedbetween dichloromethane and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over Na₂SO₄,filtered and concentrated. The residue was chromatographed on silicagel, eluting with 2% methanol in chloroform to give the title compound(0.27 g, 36% yield).

EXAMPLE 11F(2S,3S)-N-[(1S,3S,4S)-4-amino-1-benzyl-3-hydroxy-5-phenylpentyl]-3-methyl-2-{3-[(2-methyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}pentanamide

A solution containing the product from Example 11E (0.27 g, 0.4 mmol) inTHF (4 mL) was treated with an HCl solution (0.70 mL, 4 N in dioxane),heated at 60° C. for 3 hours, cooled to 25° C., and concentrated to givethe title compound as the hydrochloride salt.

EXAMPLE 11Gmethyl(1S)-1-[({(1S,2S,4S)-1-benzyl-2-hydroxy-4-[((2S)-3-methyl-2-{3-[(2-methyl-1,3-thiazol-5-yl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 11F (0.23 g, 0.4 mmol) inTHF (5 mL) was treated with the product from Example 1F (0.08 g, 0.4mmol), DEPBT (0.24 g, 0.8 mmol), and N,N-diisopropylethylamine (0.21 mL,1.2 mmol), stirred at 25° C. for 64 hours, and partitioned betweenchloroform and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over Na₂SO₄, filteredand concentrated. The residue was chromatographed on silica gel, elutingwith 2% methanol in chloroform to give the title compound (0.13 g, 44%yield). ¹H NMR (300 MHz, CDCl₃), δ ppm 0.77 (d, J=6.25 Hz, 3 H), 0.85(t, J=7.35 Hz, 4 H), 0.92 (s, 10 H), 1.00 (m, 1 H), 1.41 (m, 1 H), 2.01(m, 1 H), 2.68 (s, 3 H), 2.71 (d, J=7.35 Hz, 2 H), 2.82 (dd, J=7.35,1.84 Hz, 2 H), 3.00 (m, 1 H), 3.17 (m, 3 H), 3.66 (m, 6 H), 3.77 (d,J=8.82 Hz, 1 H), 3.94 (s, 1 H), 4.07 (m, 2 H), 4.40 (s, 2 H), 5.23 (s, 1H), 6.05 (d, J=9.19 Hz, 1 H), 6.48 (d, J=8.46 Hz, 1 H), 6.91 (s, 1 H),7.15 (m, 11 H).

EXAMPLE 12methyl(1S)-1-{[((1S,2S,4S)-1-benzyl-2-hydroxy-4-{[(2S)-3-methyl-2-(2-oxo-3-{[2-(3-pyridinyl)-1,3-thiazol-4-yl]methyl}-1-imidazolidinyl)pentanoyl]amino}-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamate

A solution containing the product from Example 8B (0.275 g, 0.56 mmol)in THF (6 mL) was treated with the product from Example 3L (0.227 g,0.61 mmol), DEPBT (0.275 g, 0.92 mmol), and N,N-diisopropylethylamine(0.55 mL, 3.16 mmol), stirred at 25° C. for 64 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was chromatographed on silica geleluting with 0-100% ethyl acetate/dichloromethane, followed by elutionwith 5% methanol in ethyl acetate to give the title compound (0.378 g,77% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.67 (d, J=6.62 Hz, 3 H),0.80 (m, 14 H), 0.94 (m, 1 H), 1.29 (m, 1 H), 1.49 (m, 2 H), 1.78 (m, 1H), 2.42 (m, 1 H), 2.68 (m, 3 H), 2.86 (m, 1 H), 3.13 (m, 4 H), 3.58 (m,4 H), 3.89 (m, 2 H), 4.12 (m, 2 H), 4.47 (s, 2 H), 4.79 (d, J=5.52 Hz, 1H), 6.80 (d, J=9.19 Hz, 1 H), 7.07 (m, 7 H), 7.52 (m, 2 H), 7.57 (s, 1H), 7.82 (d, J=8.82 Hz, 1 H), 8.29 (m, 1 H), 8.66 (dd, J=4.78, 1.84 Hz,1 H), 9.13 (d, J=1.47 Hz, 1 H).

EXAMPLE 13methyl(1S)-1-[({(1S,2S,4S)-1-benzyl-2-hydroxy-4-[((2S)-3-methyl-2-{3-[(6-methyl-3-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 13A 6-methylnicotinaldehyde

A solution of methyl 6-methylnicotinate (0.5 g, 3.3 mmol) in THF (16 mL)at 0° C. was treated dropwise with lithium aluminum hydride in THF (6.6mL, 1 M), stirred at 0° C. for 1.5 hours, treated with ethyl acetate (3mL), and stirred at 25° C. The reaction was partitioned between ethylacetate and saturated NaHCO₃, and the organic phase was washed withbrine and dried over MgSO₄, filtered and concentrated. A solution of theresidue (0.395 g) in dichloromethane (16 mL) was treated with MnO₂ (2g), stirred at 25° C. for 68 hours, and filtered through celite® to givethe title compound (0.326 g, 80% yield), which was used without furtherpurification.

EXAMPLE 13Btert-butyl(2S,3S)-3-methyl-2-{3-[(6-methyl-3-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}pentanoate

A solution containing the product from Example 3G (0.55 g, 2.39 mmol) ina mixture of benzene (6 mL) and ethanol (6 mL) was treated with theproduct from Example 13A (0.265 g, 2.19 mmol), stirred at 70° C. for 2hours, cooled to 25° C., treated with sodium borohydride (0.25 g, 6.61mmol), stirred at 25° C. for 3 hours, and partitioned between ethylacetate and saturated NaHCO₃. The organic phase was washed with brine,dried over MgSO₄, filtered and concentrated. A solution of the residue(2.19 mmol) in 1,2-dichloroethane (90 mL) was treated withN,N-disuccinimidyl carbonate (0.675 g, 2.63 mmol) and triethylamine(0.30 mL, 2.15 mmol), stirred at 25° C. for 16 hours, and partitionedwith 10% NaCO₃. The aqueous phase was extracted with additionaldichloromethane. The combined organic phase was dried over MgSO₄,filtered and concentrated. The residue was chromatographed on silica geleluting with 0-100% ethyl acetate/dichloromethane to give the titlecompound (0.392 g, 49% yield).

EXAMPLE 13C(2S,3S)-3-methyl-2-{3-[(6-methyl-3-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}pentanoate

A solution containing the product from Example 13B (0.39 g, 1.08 mmol)in dichloromethane (5 mL) was treated with trifluoracetic acid (5 mL),stirred at 25° C. for 2 hours and concentrated. The concentrate waspurified by reversed phase chromatography on a C18 column, eluting with0-100% acetonitrile/water (0.1% TFA) give the title compound (0.536 g,quantitative) as the trifluoroacetic acid salt.

EXAMPLE 13Dmethyl(1S)-1-[({(1S,2S,4S)-1-benzyl-2-hydroxy-4-[((2S)-3-methyl-2-{3-[(6-methyl-3-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 8B (0.29 g, 0.64 mmol) inTHF (6 mL) was treated with the product from Example 13C (0.27 g, 0.64mmol), DEPBT (0.300 g, 1.00 mmol), and N,N-diisopropylethylamine (0.60mL, 3.44 mmol), stirred at 25° C. for 2 hours, and partitioned betweenethyl acetate and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with0-100% ethyl acetate/dichloromethane, followed by elution with 5%methanol in ethyl acetate to give the title compound (0.345 g, 73%yield). ¹H NMR(300 MHz, DMSO-d₆), δ ppm 0.67 (d, J=6.25 Hz, 3 H), 0.85(m, 13 H), 1.21 (m, 1 H), 1.49 (m, 2 H), 1.77 (m, 1 H), 2.41 (m, 4 H),2.68 (m, 3 H), 2.84 (m, 1 H), 2.93 (m, 1 H), 3.01 (m, 2 H), 3.57 (m, 3H), 3.89 (m, 3 H), 4.11 (m, 2 H), 4.28 (s, 2 H), 4.79 (d, J=5.52 Hz, 1H), 6.80 (d, J=9.93 Hz, 1 H), 7.03 (s, 5 H), 7.17 (m, 6 H), 7.52 (m, 2H), 7.83 (d, J=8.82 Hz, 1 H), 8.35 (d, J=2.21 Hz, 1 H).

EXAMPLE 14methyl(1S)-1-[({(1S,2S,4S)-1-benzyl-4-[((2S)-3,3-dimethyl-2-{3-[(2-methyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 14Atert-butyl(2S)-3,3-dimethyl-2-{3-[(2-methyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}butanoate

A solution containing the product from Example 6F (0.82 g, 3.5 mmol) ina mixture of benzene (12 mL) and methanol (12 mL) was treated with theproduct from Example 11B (0.45 g, 3.5 mmol), heated at 50° C. for 1hour, cooled to 25° C., treated with sodium borohydride (0.27 g, 7.1mmol), stirred at 25° C. for 1 hour, quenched with sodium bicarbonatesolution and partitioned between ethyl acetate and water. The organicphase was washed with brine and dried over Na₂SO₄, filtered andconcentrated. A solution containing the residue (3.5 mmol) in toluene(20 mL) was treated with bis(4-nitrophenyl) carbonate (1.29 g, 4.2mmol), heated at reflux for 16 hours, cooled to 25° C., and partitionedbetween ethyl acetate and 10% K₂CO₃. The organic phase was washed withbrine and dried over Na₂SO₄, filtered and concentrated to give the titlecompound, which was used without further purification.

EXAMPLE 14B(2S)-3,3-dimethyl-2-{3-[(2-methyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}butanoicacid

A solution containing the product from Example 14A (3.5 mmol) indichloromethane (4 mL) was treated with trifluoracetic acid (3 mL),stirred at 25° C. for 3 hours and concentrated. The residue waschromatographed on silica gel eluting with 2% methanol in chloroform togive the title compound as the trifluoroacetic acid salt (0.88 g, 80%yield).

EXAMPLE 14Ctert-butyl(1S,2S,4S)-1-benzyl-4-[((2S)-3,3-dimethyl-2-{3-[(2-methyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-phenylpentylcarbamate

A solution containing the product from Example 11A (0.37 g, 1.0 mmol) inTHF (5 mL) was treated with the product of Example 14B (0.30 g, 1.0mmol), DEPBT (0.58 g, 1.9 mmol), and N,N-diisopropylethylamine (0.57 mL,3.3 mmol), stirred at 25° C. for 4 hours, and partitioned betweendichloromethane and 10% Na₂CO₃ solution. The organic phase was washedwith additional 10% Na₂CO₃ solution and brine, dried over Na₂SO₄,filtered and concentrated. The residue was chromatographed on silicagel, eluting with 2% methanol in chloroform to give the title compound(0.63 g, 97% yield).

EXAMPLE 14D(2S)-N-[(1S,3S,4S)-4-amino-1-benzyl-3-hydroxy-5-phenylpentyl]-3,3-dimethyl-2-{3-[(2-methyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}butamide

A solution containing the product from Example 14C (0.63 g, 0.9 mmol) inTHF (5 mL) was treated with an HCl solution (0.1.6 mL, 4 N in dioxane),heated at 60° C. for 3 hours, cooled to 25° C. and concentrated. Theresidue was treated with ethanol (10 mL) and concentrated. This processwas repeated an additional time to give the title compound as thehydrochloride salt.

EXAMPLE 14Emethyl(1S)-1-[({(1S,2S,4S)-1-benzyl-4-[((2S)-3,3-dimethyl-2-{3-[(2-methyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 14D (0.9 mmol) in THF (5mL) was treated with the product from Example 1F (0.176 g, 0.9 mmol),DEPBT (0.556 g, 1.86 mmol), and N,N-diisopropylethylamine (0.486 mL,2.79 mmol), stirred at 25° C. for 48 hours, and partitioned betweendichloromethane and 10% Na₂CO₃ solution. The organic phase was washedwith additional 10% Na₂CO₃ solution and brine, dried over Na₂SO₄,filtered and concentrated. The residue was chromatographed on silicagel, eluting with 2% methanol in chloroform to give the title compound(0.31 g, 44% yield). ¹H NMR (300 MHz, CDCl₃), δ ppm 0.94 (s, 9 H), 1.00(s, 9 H), 2.74 (m, 9 H), 3.13 (m, 2 H), 3.40 (m, 1 H), 3.63 (m, 1 H),3.68 (s, 3 H), 3.78 (d, J=9.19 Hz, 1 H), 3.83 (d, J=4.04 Hz, 1 H), 3.96(s, 1 H), 4.10 (m, 2 H), 4.44 (d, J=2.21 Hz, 2 ), 5.27 (d, J=8.46 Hz, 1H), 6.05 (d, J=9.19 Hz, 1 H), 6.14 (d, J=9.19 Hz, 1 H), 6.93 (s, 1 H),7.16 (m, 11 H).

EXAMPLE 15methyl(1S)-1-[({(1S,2S,4S)-1-benzyl-2-hydroxy-4-[((2s)-3-methyl-2-{3-[(2-methyl-3-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 15A 2-methylnicotinaldehyde

A solution of methyl 2-methylnicotinate (0.5 g, 3.3 mmol) in THF (16 mL)at 0° C. was treated dropwise with lithium aluminum hydride in THF (6.6mL, 1 M), stirred at 0° C. for 1.5 hours, treated with ethyl acetate (3mL), warmed to 25° C., and partitioned between ethyl acetate andsaturated NaHCO₃. The organic phase was washed with brine, dried overMgSO₄, filtered and concentrated. A solution of the residue (0.391 g) indichloromethane (16 mL) was treated with MnO₂ (2 g), stirred at 25° C.for 68 hours, filtered through celite®, and the solvent was evaporatedto give the title compound (0.303 g, 75% yield), which was used withoutfurther purification.

EXAMPLE 15Btert-butyl(2S,3S)-3-methyl-2-{3-[(2-methyl-3-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}pentanoate

A solution containing the product from Example 3G (2.4 g, 10.43 mmol) indichloromethane (24 mL) was treated with the product from Example 15A(1.3 g, 10.74 mmol) and MgSO₄ (4.6 g, 38.21 mmol), stirred at 25° C. for2.5 hours, filtered and concentrated. A solution of the residue inmethanol (24 mL) at 0° C. was treated with sodium borohydride (0.5 g,13.2 mmol), and stirred at 25° C. for 3 hours. The solvent wasconcentrated and the reaction was partitioned between ethyl acetate andsaturated NaHCO₃, and the organic phase was washed with brine and driedover MgSO₄, filtered and concentrated. A solution of the residue (3.4 g)in 1,2 dichloroethane (30 mL was treated with bis(4-nitrophenyl)carbonate (3.8 g, 12.5 mmol), heated at 60° C. for 16 hours, andpartitioned between ethyl acetate and saturated NaHCO₃. The organicphase was washed with brine, dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting withethyl acetate to give the title compound (2.31 g, 60% yield).

EXAMPLE 15C(2S,3S)-3-methyl-2-{3-[(2-methyl-3-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}pentanoicacid

A solution containing the product from Example 15B (2.3 g, 6.37 mmol) indichloromethane (15 mL) was treated with trifluoracetic acid (15 mL),stirred at 25° C. for 5.5 hours and concentrated to give the titlecompound (3.42 g) as the trifluoroacetic acid salt, which was usedwithout further purification.

EXAMPLE 15Dmethyl(1S)-1-[({(1S,2S,4S)-1-benzyl-2-hydroxy-4-[((2S)-3-methyl-2-{3-[(2-methyl-3-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 8B (2.0 g, 4.40 mmol) inDMF (10 mL) was treated with the product from Example 15C (1.34 g, 4.39mmol), EDAC (1.01 g, 5.27 mmol), HOBT (0.7 g, 5.19 mmol), and NMM (0.96mL, 8.72 mmol), stirred at 25° C. for 16 hours, treated with Example 15C(0.13 g), EDAC (0.5 g), HOBT (0.35 g), NMM (1 mL), and DMF (5 mL),stirred for 64 hours at 25° C. and concentrated. The concentrate waspartitioned between ethyl acetate and saturated NaHCO₃. The organicphase was washed with brine, dried over Na₂SO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with0-4% methanol/dichloromethane to give the title compound (1.76 g, 54%yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.68 (d, J=6.62 Hz, 3 H), 0.81(m, 15 H), 1.26 (m, 1 H), 1.49 (m, 2 H), 1.78 (m, 1 H), 2.45 (m, 5 H),2.70 (m, 3 H), 2.90 (m, 2 H), 3.04 (m, 2 H), 3.59 (m, 4 H), 3.87 (m, 2H), 4.13 (m, 2 H), 4.31 (s, 2 H), 4.79 (d, J=5.52 Hz, 1 H), 6.80 (d,J=9.19 Hz, 1 H), 7.05 (s, 3 H), 7.19 (m, 5 H), 7.51 (m, 2 H), 7.86 (d,J=8.82 Hz, 1 H), 8.36 (d, J=3.68 Hz, 1 H).

EXAMPLE 16methyl(1S)-1-[({(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 2C (1.0 g, 1.88 mmol) inTHF (19 mL) was treated with the product from Example 10B (0.83 g, 1.98mmol), DEPBT (0.84 g, 2.8 mmol), and N,N-diisopropylethylamine (1.6 mL,9.2 mmol), stirred at 25° C. for 16 hours, and partitioned between amixture of dichloromethane and ethyl acetate (2:1, respectively) and 10%Na₂CO₃ solution. The organic phase was washed with additional 10% Na₂CO₃solution and brine, dried over MgSO₄, filtered and concentrated. Theresidue was chromatographed on silica gel eluting with 0-100% ethylacetate/dichloromethane, followed by elution with 0-5% methanol in ethylacetate to give the title compound (1.15 g, 75% yield). ¹H NMR (300 MHz,DMSO-d₆), δ ppm 0.83 (s, 9 H), 0.90 (s, 9 H), 1.55 (m, 2 H), 2.38 (q,J=9.44 Hz, 1 H), 2.46 (s, 3 H), 2.57 (m, 1 H), 2.67 (d, J=7.35 Hz, 2 H),2.79 (m, 1 H), 2.97 (m, 1 H), 3.09 (q, J=8.95 Hz, 1 H), 3.21 (m, 1 H),3.50 (s, 3 H), 3.67 (m, 1 H), 3.85 (d, J=9.93 Hz, 1 H), 4.12 (m, 3 H),4.35 (m, 2 H), 4.54 (d, J=7.72 Hz, 1 H), 6.63 (d, J=9.56 Hz, 1 H), 7.09(m, 7 H), 7.22 (d, J=8.09 Hz, 2 H), 7.31 (m, 1 H), 7.49 (d, J=9.56 Hz, 1H), 7.69 (t, J=7.54 Hz, 1 H), 7.86 (m, 5 H), 8.63 (d, J=4.78 Hz, 1 H).

EXAMPLE 17methyl(1S)-1-{[((1S,2S,4S)-1-benzyl-2-hydroxy-4-{[(2S)-2-(3-{[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamateEXAMPLE 17A methyl 6-(hydroxymethyl)-2-pyridinecarboxylate

A suspension of dimethyl 2,6-pyridine-dicarboxylate (50 g, 0.25 mol) inmethanol (400 mL) and tetrahydrofuran (150 mL) was heated to dissolveand while the solution was still hot, it was treated in portions withsodium borohydride (9.1 g, 0.24 mol). The mixture was stirred for 1 hourafter the addition, cooled to 25° C., quenched with 10% citric acid (80mL), stirred for 15 minutes, filtered, and concentrated. A solution ofthe concentrate in dichloromethane was dried over sodium sulfate,filtered, and concentrated. A solution of the residue in hot ethylacetate was allowed to stand for 16 hours at 25° C. The resultingprecipitate (23 g) was collected by filtration. The mother liquor wasconcentrated and the resulting solid was purified by flashchromatography on silica gel eluting with 10% methanol indichloromethane to give the crude white solid (24 g). The solid wascrystallized in ethyl acetate to give a total yield of the titlecompound (36 g, 84% yield).

EXAMPLE 17B methyl 6-formyl-2-pyridinecarboxylate

A solution of the product from Example 17A (8 g, 48 mmol) indichloromethane (200 mL) was treated with electrolytic manganese dioxide(41.67 g, 0.48 mol). The mixture was stirred for 4 days at 25° C. andfiltered through celite. The filtrate was concentrated under reducedpressure and the residue was purified by chromatography on silica geleluting with 5% methanol in dichloromethane to give the title compoundas a white solid (6.9 g, 87% yield).

EXAMPLE 17C methyl6-{[(2-{[(1S)-1-(tert-butoxycarbonyl)-2,2-dimethylpropyl]amino}ethyl)amino]methyl}-2-pyridinecarboxylate

A suspension containing the product from Example 17B (6 g, 36.4 mmol),the product from Example 6F (8.37 g, 36.4 mmol), and magnesium sulfate(21.9 g, 0.18 mol) in dichloromethane (80 mL) was stirred at 25° C. for4 hours, filtered, and concentrated. A solution of the residue inmethanol (80 mL) was treated with sodium borohydride (1.58 g, 41.9 mmol)at 0° C., stirred 0.5 hour at 0° C., quenched with acetone (2 mL),concentrated, treated with 1M sodium bicarbonate and extracted withethyl acetate. The organic phase was concentrated and the residue waschromatographed on silica gel eluting with 8% methanol indichloromethane to give the title compound (10.27 g).

EXAMPLE 17D methyl6-({3-[(1S)-1-(tert-butoxycarbonyl)-2,2-dimethylpropyl]-2-oxo-1-imidazolidinyl}methyl)-2-pyridinecarboxylate

A solution of the product from Example 17C (10.27 g, 27.1 mmol), bis(4-nitrophenyl) carbonate (8.24 g, 27.1 mmol), in toluene (100 mL) washeated at 110° C. for 16 hours, cooled to 25° C., treated with 1M sodiumbicarbonate, and extracted with ethyl acetate. The organic phase layerwas concentrated and the residue was purified by flash chromatography onsilica gel eluting with 60% ethyl acetate in hexane to give the titlecompound as a white solid (9.44 g, 64% yield).

EXAMPLE 17Etert-butyl(2S)-2-(3-{[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoate

A solution of the product from Example 17D (9 g, 22.2 mmol) intetrahydrofuran (200 mL) at 0° C. was treated with a solution ofmethylmagnesium bromide in diethyl ether (3M, 37 mL, 111 mmol), stirredfor 1.5 hours at 0° C., quenched with 10% citric acid (20 mL), andextracted with ethyl acetate. The organic phase was concentrated, andthe residue was purified by flash chromatography on silica gel elutingwith 20-70% ethyl acetate in hexane to give the title compound (7.2 g,80% yield).

EXAMPLE 17F(2S)-2-(3-{[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]methyl}-2-oxo-1-imidazolidinyl-3,3-dimethylbutanoicacid

The product from Example 17E (7.2 g, 17.8 mmol) at 25° C. was treatedwith 90% trifluoroacetic acid in water (30 mL). The reaction mixture wasstirred at 25° C. for 3 hours and concentrated. A solution of theresidue in water (2 mL) was chromatographed on silica gel eluting with5% methanol/dichloromethane to give the title compound as thetrifluoroacetic acid salt (7.4 g, 89.9% yield).

EXAMPLE 17Gmethyl(1S)-1-{[((1S,2S,4S)-1-benzyl-2-hydroxy-4-{[(2S)-2-(3-{[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamate

A solution containing the product from Example 8B (1.7 g, 3.73 mmol) inTHF (25 mL) was treated with the product from Example 17F (1.8 g, 3.88mmol), DEPBT (2.32 g, 7.46 mmol), and triethylamine (1.35 mL, 9.32mmol), stirred at 25° C. for 16 hours, quenched with sodium bicarbonatesolution (1M), and extracted with ethyl acetate. The organic phase layerwas decanted and concentrated. The residue was chromatographed on asilica gel column eluting with 2% methanol/ethyl acetate to give thetitle compound (1.73 g, 57% yield). ¹H NMR (300 MHz, CD₃OD) δ ppm 0.91(s, 9 H), 0.95 (s, 9 H), 1.24 (m, 1 H), 1.35 (m, 2 H), 1.53 (s, 6 H),1.66 (m, 1 H), 2.01 (s, 1 H,) 2.42 (m, 1 H), 2.87 (m, 2 H), 3.08 (m, 1H), 3.24 (m, 1 H), 3.66 (s, 2 H), 3.76 (m, 1 H), 3.92 (s, 1 H), 3.98 (s,1 H), 4.09 (m, 1 H), 4.25 (dd, J=8.64, 7.17 Hz, 1 H), 4.36 (m, J=8.82Hz, 1 H), 4.43 (s, 1 H), 4.58 (s, 1 H), 4.63 (s, 1 H), 7.14 (m, 11 H),7.53 (d, J=6.99 Hz, 1 H), 7.77 (t, J=7.91 Hz, 1 H).

EXAMPLE 18methyl(1S)-1-[({(1S,3S,4S)-3-hydroxy-4-[((2S)-3-methyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 2C (0.01 g, 0.019 mmol)in THF (0.2 mL) was treated with the product from Example 7B (0.009 g,0.021 mmol), DEPBT (0.009 g, 0.030 mmol), and N,N-diisopropylethylamine(0.016 mL, 0.092 mmol), stirred at 25° C. for 16 hours and partitionedbetween a mixture of dichloromethane, ethyl acetate (2:1, respectively)and 10% Na₂CO₃ solution. The organic phase was washed with additional10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was purified by reversed phase chromatographyon a C18 column eluting with a gradient starting with 5-100%acetonitrile in water (0.1% TFA). The product was partitioned between amixture of dichloromethane and ethyl acetate (2:1, respectively) andsaturated NaHCO₃ solution. The organic phase was washed with brine,dried over MgSO₄, filtered and concentrated to give the title compound(0.0076 g, 51% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.82 (m, 18 H),1.31 (m, 3 H), 1.52 (m, 2 H), 1.80 (m, 1 H), 2.45 (s, 3 H), 2.67 (m, 4H), 3.09 (m, 4 H), 3.50 (s, 1 H), 3.66 (m, 1 H), 3.84 (d, J=9.93 Hz, 1H), 3.93 (d, J=11.03 Hz, 1 H), 4.14 (m, 1 H), 4.35 (s, 1 H), 4.67 (d,J=7.35 Hz, 1 H), 6.64 (d, J=9.93 Hz, 1 H), 7.21 (m, 12 H), 7.66 (t,J=7.72 Hz, 1 H), 7.86 (m, 4 H), 8.63 (d, J=4.78 Hz, 1 H).

EXAMPLE 19methyl(1S)-1-{[((1S,2S,4S)-1-benzyl-4-{[(2S)-3,3-dimethyl-2-(2-oxo-3-{[2-(3-pyridinyl-1,3-thiazol-4-yl]methyl)}-1-imidazolidinyl)butanoyl]amino}-2-hydroxy-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamateEXAMPLE 19A ethyl 2-(3-pyridinyl)-1,3-thiazole-4-carboxylate

A solution containing thionicotinamide (30 g, 217.1 mmol) in ethanol(540 mL) was treated with ethyl bromopyruvate (30.3 mL, 241.4 mmol),heated at 70° C. for 3 hours, cooled to 25° C., concentrated andpartitioned between chloroform and saturated NaHCO₃. The organic phasewas washed with brine, dried over MgSO₄, filtered and concentrated. Theresidue was chromatographed on silica gel eluting with chloroform andthen with 15% methanol in chloroform containing 1% ammonium hydroxide togive the product (36.3 g, 71% yield).

EXAMPLE 19B 2-(3-pyridinyl)-1,3-thiazole-4-carbaldehyde

A solution containing the product from Example 19A (20 g, 85.5 mmol) indichloromethane (340 mL) was treated dropwise with DIBAL (86 mL, 1 M indichloromethane) at −78° C., stirred at −78° C. for 2 hours, treatedwith DIBAL (43 mL, 1 M in dichloromethane), stirred at −78° C. for 1hour, treated with methanol (20 mL) at −78° C., warmed to 25° C.,treated with dichloromethane (250 mL), saturated aqueous sodiumpotassium tartrate (350 mL), and pH 7 buffer (300 mL), stirredvigorously with a mechanical stirrer for 16 hours, and filtered throughcelite®. The aqueous phase was washed with chloroform, and the combinedorganic phase was washed with brine and dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting 0-4%methanol/chloroform to give the title compound (11.61 g, 71% yield).

EXAMPLE 19Ctert-butyl(2S)-3,3-dimethyl-2-(2-oxo-3-{[2-(3-pyridinyl)-1,3-thiazol-4-yl]methyl}-1-imidazolidinyl)butanoate

A solution containing the product from Example 6F (0.855 g, 3.72 mmol)in a mixture of benzene (10 mL) and ethanol (10 mL) was treated with theproduct from Example 19B (0.70 g, 3.72 mmol), heated at 70° C. for 1hour, cooled to 25° C. and treated with sodium borohydride (0.422 g,11.16 mmol), stirred at 25° C. for 2 hours, quenched with sodiumbicarbonate solution and partitioned between ethyl acetate and water.The organic phase was washed with brine, dried over MgSO₄, filtered andconcentrated. A solution of the residue (3.72 mmol) in toluene (85 mL)was treated with bis(4-nitrophenyl) carbonate (1.36 g, 4.47 mmol),heated at 100° C. for 24 hours, cooled to 25° C., and partitionedbetween ethyl acetate and 10% K₂CO₃. The organic phase was washedseveral times with 10% K₂CO₃, and with brine, dried over MgSO₄, filteredand concentrated. The residue was chromatographed on silica gel elutingwith 40% chloroform in hexanes to give the title compound (0.61 g, 39%yield).

EXAMPLE 19D(2S)-3,3-dimethyl-2-(2-oxo-3-{[2-(3-pyridinyl)-1,3-thiazol-4-yl]methyl}-1-imidazolidinyl)butanoicacid

A solution containing the product from Example 19C (0.61 g, 1.42 mmol)in dichloromethane (7 mL) was treated with trifluoracetic acid (4 mL),stirred at 25° C. for 1 hour, concentrated, and azeotroped several timeswith toluene to give the title compound as the trifluoroacetic acidsalt, which was used without further purification.

EXAMPLE 19Emethyl(1S)-1-{[((1S,2S,4S)-1-benzyl-4-{[(2S)-3,3-dimethyl-2-(2-oxo-3-{[2-(3-pyridinyl)-1,3-thiazol-4-yl]methyl}-1-imidazolidinyl)butanoyl]amino}-2-hydroxy-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamate

A solution containing the product from Example 8B (1.4 g, 3.08 mmol) inTHF (30 mL) was treated with the product from Example 19D (1.5 g, 3.07mmol), DEPBT (1.4 g, 4.68 mmol), and N,N-diisopropylethylamine (2.75 mL,15.78 mmol), stirred at 25° C. for 16 hours, and partitioned betweendichloromethane and 10% Na₂CO₃ solution. The organic phase was washedwith additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was chromatographed on silica geleluting with 0-100% ethyl acetate/dichloromethane, followed by 0-5%methanol in ethyl acetate. The product was then purified by reversedphase chromatography on a C18 column eluting with a gradient startingwith 5-100% acetonitrile in water (0.1% TFA). The product waspartitioned between dichloromethane and saturated NaHCO₃ solution. Theorganic phase was washed brine, dried over MgSO₄, filtered andconcentrated to give the title compound (1.49 g, 60% yield). ¹H NMR (300MHz, DMSO-d₆), δ ppm 0.84 (s, 9 H), 0.86 (s, 9 H), 1.49 (m, 2 H), 2.39(m, 2 H), 2.62 (m, 1 H), 2.72 (d, J=6.99 Hz, 2 H), 3.16 (m, 3 H), 3.57(m, 4 H), 3.91 (d, J=9.56 Hz, 1 H), 3.98 (s, 1 H), 4.17 (m, 2 H), 4.48(m, 2 H), 4.80 (d, J=5.52 Hz, 1 H), 6.81 (d, J=9.19 Hz, 1 H), 6.94 (m, 1H), 7.04 (m, 4 H), 7.15 (m, 5 H), 7.52 (m, 2 H), 7.59 (s, 1 H), 7.88 (d,J=9.56 Hz, 1 H), 8.30 (m, 1 H), 8.66 (dd, J=4.78, 1.47 Hz, 1 H), 9.14(d, J=1.47 Hz, 1 H).

EXAMPLE 20methyl(1S)-1-({[(1S,2S,4S)-1-benzyl-4-({(2S)-3,3-dimethyl-2-[2-oxo-3-(3-pyridinylmethyl)-1-imidazolidinyl]butanoyl}amino)-2-hydroxy-5-phenylpentyl]amino}carbonyl)-2,2-dimethylpropylcarbamateEXAMPLE 20A(2S)-3,3-dimethyl-2-[2-oxo-3-(3-pyridinylmethyl)-1-imidazolidinyl]butanoicacid

A solution containing the product from Example 6F (0.10 g, 0.43 mmol) ina mixture of benzene (1.6 mL) and methanol (1.66 mL) was treated withpyridine-3-carboxaldehyde (0.041 mL, 0.43 mmol), stirred at 50° C. for18 hours, cooled to 25° C., treated with sodium borohydride (0.033 g,0.87 mmol), stirred at 25° C. for 1 hour, quenched with saturatedNaHCO₃, stirred for 1 hour, and partitioned between ethyl acetate andsaturated NaHCO₃. The organic phase was washed with brine, dried overMgSO₄, filtered and concentrated. A solution of the residue (0.127 g,0.40 mmol) in 1,2-dichloroethane (7 mL) was treated withN,N-disuccinimidyl carbonate (0.134 g, 0.52 mmol) and triethylamine(0.07 mL, 0.50 mmol), stirred at 25° C. for 16 hours, diluted withchloroform and partitioned with 10% Na₂CO₃. The organic phase was washedwith brine, dried over MgSO₄, filtered and concentrated. A solution ofthe residue (0.146 g) in dichloromethane (2 mL) was treated withtrifluoracetic acid (2 mL), stirred at 25° C. for 2 hours, concentrated,and azeotroped with toluene several times to give the title compound(0.252 g), as the trifluoroacetic acid salt.

EXAMPLE 20Bmethyl(1S)-1-({[(1S,2S,4S)-1-benzyl-4-({(2S)-3,3-dimethyl-2-[2-oxo-3-(3-pyridinylmethyl)-1-imidazolidinyl]butanoyl}amino)-2-hydroxy-5-phenylpentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate

A solution containing the product from Example 8B (2.0 g, 4.40 mmol) inDMF (10 mL) was treated with the product from Example 20A (1.78 g, 4.39mmol), EDAC (1.01 g, 5.27 mmol), HOBT (0.7 g, 5.19 mmol), and NMM (0.96mL, 8.72 mmol), stirred at 25° C. for 16 hours, additional acid (0.17g), EDAC (0.42 g), HOBT (0.3 g), NMM (0.5 mL), and DMF (5 mL) was added,stirred for 16 hours at 25° C., and concentrated. The reaction waspartitioned between ethyl acetate and water. The organic phase waswashed with brine and dried over Na₂SO₄, filtered and concentrated. Theresidue was chromatographed on silica gel eluting with 3% methanol indichloromethane to give the title compound (2.0 g, 62% yield). ¹H NMR(300 MHz, DMSO-d₆), δ ppm 0.85 (d, J=1.47 Hz, 18 H), 1.01 (m, 1 H), 1.51(m, 2 H), 2.39 (m, 2 H), 2.66 (m, 1 H), 2.72 (d, >6.99 Hz, 2 H), 2.90(m, 2 H), 3.21 (m, 1 H), 3.58 (m, 3 H), 3.91 (d, J=9.93 Hz, 1 H), 3.96(s, 1 H), 4.19 (m, 2 H), 4.34 (d, J=2.94 Hz, 2 H), 4.80 (d, J=5.52 Hz, 1H), 6.81 (d, J=9.93 Hz, 1 H), 7.02 (m, 5 H), 7.14 (m, 5 H), 7.40 (dd,J=8.09, 4.78 Hz, 1 H), 7.50 (d, J=9.19 Hz, 1 H), 7.67 (m, 1 H), 7.89 (d,J=9.19 Hz, 1 H), 8.51 (d, J=2.94 Hz, 2 H).

EXAMPLE 21methyl(1S)-1-[({(1S,3S,4S)-3-hydroxy-4-[((2S)-3-methyl-2-{3-[(2-methyl-3-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 2C (1.1 g, 2.07 mmol) inTHF (20 mL) was treated with the product from Example 15C (0.87 g, 2.07mmol), DEPBT (0.93 g, 3.11 mmol), and N,N-diisopropylethylamine (1.8 mL,10.33 mmol), stirred at 25° C. for 3 hours, and partitioned betweenethyl acetate and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was purified by chromatography on silica geleluting with a gradient starting with 0-100% ethylacetate/dichloromethane, followed by 0-10% methanol in ethyl acetate togive the title compound (1.17 g, 69% yield). ¹H NMR (300 MHz, DMSO-d₆),δ ppm 0.83 (m, 18 H), 1.29 (m, 1 H), 1.53 (m, 2 H), 1.80 (m, 1 H), 2.48(s, 3 H), 2.72 (m, 3 H), 2.96 (m, 3 H), 3.50 (s, 3 H), 3.65 (m, 1 H),3.84 (d, J=9.93 Hz, 1 H), 3.94 (d, J=11.03 Hz, 1 H), 4.15 (m, 2 H), 4.32(s, 2 H), 4.67 (d, J=7.35 Hz, 1 H), 6.64 (d, J=9.93 Hz, 1 H), 7.09 (m, 5H), 7.22 (m, 3 H), 7.31 (m, 2 H), 7.52 (dd, J=7.72, 1.47 Hz, 1 H), 7.86(m, 5 H), 8.36 (dd, J=4.78, 1.47 Hz, 1 H), 8.63 (d, J=4.41 Hz, 1 H).

EXAMPLE 22methyl(1S)-1-[({(1S,3S,4S)-1-benzyl-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 22Atert-butyl(1S,3S,4S)-1-benzyl-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenylpentylcarbamate

A solution of the product from Example 6A (3.0 g, 7.81 mmol) in THF (80mL) was treated with the product from Example 10D (2.93 g, 8.57 mmol),DEPBT (3.5 g, 11.71 mmol), and N,N-diisopropylethylamine (7 mL, 40.19mmol) and the mixture was stirred at 25° C. for 3 hours. The mixture waspartitioned between ethyl acetate and 10% Na₂CO₃ solution. The organicphase was washed with additional 10% Na₂CO₃ solution and brine, driedover MgSO₄, filtered and concentrated. The product was used withoutfurther purification.

EXAMPLE 22Bmethyl(1S)-1-[({(1S,3S,4S)-1-benzyl-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution of the product from Example 22A (7.81 mmol) indichloromethane (20 mL) was treated with trifluoroacetic acid (20 mL),and the mixture was stirred at 25° C. for 1 hour. The solvent wasconcentrated and the reaction was partitioned between ethyl acetate and10% Na₂CO₃, and the organic phase was washed with brine and dried overMgSO₄, filtered and concentrated. A solution of the residue (7.81 mmol)in THF (80 mL) was treated with the product from Example 1F (1.6 g, 8.47mmol), DEPBT (3.5 g, 11.71 mmol), and N,N-diisopropylethylamine (6.8 mL,39.04 mmol) and the mixture was stirred at 25° C. for 5 hours. Themixture was partitioned between ethyl acetate and 10% Na₂CO₃ solution.The organic phase was washed with additional 10% Na₂CO₃ solution andbrine, dried over MgSO₄, filtered and concentrated. The product waspurified by chromatography on silica gel eluting with a gradientstarting with 0-100% ethyl acetate/dichloromethane, followed by 0-10%methanol in ethyl acetate. The product was then purified by reversedphase chromatography on a C18 column eluting with a gradient startingwith 5-100% acetonitrile in water (0.1% TFA). The product was,partitioned between ethyl acetate and 10% Na₂CO₃ solution. The organicphase was washed brine, dried over MgSO₄, filtered and concentrated togive the title compound (1.32 g, 23% yield). ¹H NMR (300 MHz, DMSO-d₆),δ ppm 0.82 (s, 9 H), 0.91 (s, 9 H), 1.25 (m, 1 H), 1.51 (m, 2 H), 2.36(m, 1 H), 2.46 (s, 3 H), 2.70 (m, 3 H), 2.96 (m, 1 H), 3.09 (m, 1 H),3.23 (m, 1 H), 3.55 (s, 3 H), 3.65 (m, 1 H), 3.83 (d, J=9.93 Hz, 1 H),4.14 (m, 3 H), 4.35 (m, 2 H), 4.50 (d, J=7.72 Hz, 1 H), 6.64 (d, J=9.93Hz, 1 H), 7.09 (m, 12 H), 7.47 (d, J=9.19 Hz, 1 H), 7.71 (m, 2 H).

EXAMPLE 23methyl(1S)-1-[({(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl(methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 23Abenzyl(2S)-3-[4-(benzyloxy)phenyl]-2-(dibenzylamino)propanoate

A suspension of L-Tyrosine (20 g, 110.4 mmol) in a mixture of water andethanol (2:1, respectively, 120 mL) was treated with potassium carbonate(76.3 g, 552.1 mmol) and benzyl chloride (63.5 mL, 551.8 mmol), and themixture was heated at reflux for 68 hours. The reaction was cooled to25° C., treated with a mixture of hexanes and THF (1:1, 500 mL),followed by water. The mixture was partitioned and the organic phase waswashed two times with a mixture of water and methanol (2:1,respectively) and then with brine, dried over MgSO₄, filtered andconcentrated. The crude product (53.5 g) was used without furtherpurification.

EXAMPLE 23B(4S)-5-[4-(benzyloxy)phenyl]-4-(dibenzylamino)-3-oxopentanenitrile

A solution of sodium bis(trimethylsilyl) amide (1 M in THF, 330 mL) at−45° C., was treated dropwise with acetonitrile (18.8 mL, 360 mmol) andthe mixture was stirred for 15 minutes at −45° C. and then cooled to −78° C., treated dropwise with a solution of the product from Example 23A(53.5 g, 110 mmol) in THF (150 mL), warmed to −45° C., stirred for 1hour, treated with solid NH₄Cl (40 g), warmed to 5° C., treated withwater, warmed to 25° C. and partitioned between ethyl acetate and water.The organic phase was washed with brine and dried over MgSO₄, filteredand concentrated. Precipitation from ethanol gave the product (19.0 g,36% yield).

EXAMPLE 23C(2S)-5-amino-1-[4-(benzyloxy)phenyl]-2-(dibenzylamino)-6-phenyl-4-hexen-3-one

A solution containing the product from Example 23B (19.0 g, 40.1 mmol)in THF (48 mL) was treated dropwise with a solution of benzyl magnesiumbromide (120 mL, 1 M in ether) at 0° C. The mixture was allowed to warmto 25° C. and was stirred for 16 hours. The reaction was cooled to 0° C.and quenched with 10% citric acid, followed by partitioning betweenethyl acetate and water. The organic phase was washed with brine anddried over MgSO₄, filtered and concentrated to give the crude product(23.2 g), which was used without further purification.

EXAMPLE 23D(2S,3S,5S)-5-amino-1-[4-(benzyloxy)phenyl]-2-(dibenzylamino)-6-phenyl-3-hexanol

(i) A suspension of NaBH₄ (6.07 g, 160.4 mmol) in THF (170 mL) at −10°C. was treated with methanesulfonic acid (26.0 mL, 401.0 mmol) dropwise.After complete addition, a solution containing the product from Example23C (23.2 g, 40.1 mmol) in a mixture of THF (60 mL) and water (6 mL) wasadded and the mixture was stirred at −10° C. for 18 hours.

(ii) A suspension of NaBH₄ (6.07 g, 160.4 mmol) in THF (170 mL) at 0° C.was treated dropwise with trifluoroacetic acid (15.4 mL, 200.5 mmol),stirred at 0° C. for 30 minutes, treated with the solution from step(i), warmed to 25° C., stirred for 3 hours, treated with a mixture ofNaBH₄ (6.07 g, 160.4 mmol) and trifluoroacetic acid (15.4 mL, 200.5mmol) prepared as described above, warmed to 25° C. and stirred for 2hours. The reaction was cooled to 0° C. and quenched cautiously by slowaddition of NaOH solution (300 mL, 3 N), followed by partitioningbetween tert-butyl methyl ether and water. The organic phase was washedwith NaOH solution (0.5 N), NH₄Cl solution, and brine, dried over MgSO₄,filtered and concentrated to give the crude product (22.9 g), which wasused without further purification.

EXAMPLE 23Etert-butyl(1S,3S,4S)-1-benzyl-5-[4-(benzyloxy)phenyl]-4-(dibenzylamino)-3-hydroxypentylcarbamate

A solution containing the product from Example 23D (22.9 g, 40.1 mmol)intert-butyl methyl ether (200 mL) was treated with 10% K₂CO₃ (95 mL)and di-tert-butyl dicarbonate (14.0 g, 64.2 mmol), and stirred at 25° C.for 2 hours. The organic phase layer was washed with water and brine,dried over MgSO₄, filtered and concentrated. The residue waschromatographed on silica gel eluting with 20% hexanes in chloroform andthen with 10% ethyl acetate in chloroform to give the title compound(12.3 g, 46% yield).

EXAMPLE 23F tert-butyl(1S,3S,4S)-4-amino-1-benzyl-3-hydroxy-5-(4-hydroxyphenyl)pentylcarbamate

A solution containing the product from Example 23E (12.3 g, 18.4 mmol)in THF (169 mL) was treated with 10% Pd on carbon (2.5 g) and ammoniumformate (6.9 g, 109.4 mmol) and the mixture was heated at reflux for 1.5hours. Additional 10% Pd on carbon (1.25 g) and NH₄CO₂H (3.45 g) wereadded and the mixture was heated at reflux for 2.5 hours. The reactionwas concentrated and partitioned between chloroform and water and thesolution was adjusted to pH 10 with NaHCO₃ solution. The organic phasewas washed with brine and dried over MgSO₄, filtered and concentrated togive the title compound (6.1 g, 82% yield), which was used withoutfurther purification.

EXAMPLE 23Gbenzyl(1S,2S,4S)-4-[(tert-butoxycarbonyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)-5-phenylpentylcarbamate

A solution containing the product from Example 23F (6.1 g, 15.2 mmol) inTHF (150 mL) was treated with N-(benzyloxycarbonyloxy)succinimide (3.4g, 13.6 mmol) and N,N-diisopropylethylamine (3.3 mL, 19.0 mmol), stirredat 25° C. for 68 hours and concentrated. The residue was chromatographedon silica gel eluting with 33% ethyl acetate in chloroform and then with10% methanol in chloroform to give the title compound (5.1 g, 63%yield).

EXAMPLE 23H4-{(2S,3S,5S)-2-{[(benzyloxy)carbonyl]amino}-5-[(tert-butoxycarbonyl)amino]-3-hydroxy-6-phenylhexyl}phenyltrifluoromethanesulfonate

A solution containing the product from Example 23G (5.1 g, 9.6 mmol) indichloromethane (50 mL) was treated withN-Phenyltrifluoromethanesulfonimide (4.1 g, 11.5 mmol) and DMAP (1.4 g,11.5 mmol), heated at reflux for 1 hour, cooled to 25° C. andchromatographed on silica gel eluting with 0-50% ethylacetate/chloroform to give the title compound (4.7 g, 74% yield).

EXAMPLE 23Ibenzyl(4S,5S)-5-{(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}-2,2-dimethyl-4-{4-[(trifluoroacetyl)oxy]benzyl}-1,3-oxazolidine-3-carboxylate

A solution containing the product from Example 23H (4.7 g, 7.1 mmol) in2,2-dimethoxypropane (70 mL) was treated with p-toluenesulfonic acidmonohydrate (0.067 g, 0.35 mmol), and the mixture was stirred at 25° C.for 1 hour. Triethylamine (0.3 mL, 2.15 mmol) was added, and thereaction was partitioned between ethyl acetate and water. The organicphase was washed with brine and dried over MgSO₄, filtered andconcentrated to give the title compound (4.83 g, 97% yield), which wasused without further purification.

EXAMPLE 23Jbenzyl(1S,2S,4S)-4-[(tert-butoxycarbonyl)amino]-2-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentylcarbamate

A solution containing the product from Example 23I (2.65 g, 3.75 mmol)in DMF (20 mL) was treated with LiCl (1.6 g, 37.74 mmol),dichlorobis(triphenylphosphine)palladium(II) (0.5 g, 0.71 mmol), and2-tri-n-butylstannylpyridine (2.6 mL, 11.30 mmol), heated at 100° C. for16 hours, cooled and partitioned between ethyl acetate and water. Theorganic phase was washed with brine and dried over MgSO₄, filtered andconcentrated. A solution of the residue in THF (30 mL) and aqueous HCl(30 mL, 1 N) was stirred at 50° C. for 48 hours, cooled to 0° C. andadjusted to pH 8 with 3 N NaOH solution. The reaction mixture waspartitioned between ethyl acetate and water, and the organic phase waswashed with brine and dried over MgSO₄, filtered and concentrated. Asolution of the residue in THF (30 mL) was treated with triethylamine (1mL, 13.6 mmol) and di-tert-butyl dicarbonate (0.82 g, 3.75 mmol),stirred at 25° C. for 16 hours, and partitioned between ethyl acetateand saturated NaHCO₃. The organic phase was washed with brine and driedover MgSO₄, filtered and concentrated. The residue was chromatographedon silica gel eluting with 0-100% ethyl acetate/dichloromethane to givethe title compound (0.568 g, 25% yield).

EXAMPLE 23K benzyl(2S)-3-(4-bromophenyl)-2-(dibenzylamino)propanoate

A suspension of L-p-bromophenylalanine (5 g, 20.5 mmol) in a mixture ofwater and ethanol (2:1, respectively, 20 mL) was treated with potassiumcarbonate (9.3 g, 67.3 mmol) and benzyl chloride (7.77 mL, 67.5 mmol),heated at reflux for 16 hours, cooled to 25° C. and treated with amixture of hexanes and THF (1:1, 100 mL), followed by addition of water.The mixture was partitioned and the organic phase was washed two timeswith a mixture of water and methanol (2:1, respectively) and then withbrine, dried over MgSO₄, filtered and concentrated. The crude product(11.23 g) was used without further purification.

EXAMPLE 23Lbenzyl(2S)-2-(dibenzylamino)-3-[4-(2-pyridinyl)phenyl]propanoate

A solution containing the product from Example 23K (11.0 g, 20.5 mmol)in DMF (90 mL) was treated with LiCl (8 g, 188.7 mmol),tetrakis(triphenylphosphine)palladium(0) (5 g, 4.3 mmol), and2-tri-n-butylstannylpyridine (22 g, 59.8 mmol), heated at 80° C. for 16hours, cooled, filtered and concentrated. The residue was partitionedbetween ethyl acetate and water, and the organic phase was washed withbrine and dried over MgSO₄, filtered and concentrated. The residue waspurified by chromatography on silica gel eluting with a gradient 0-25%ethyl acetate/hexanes to give the title compound (7.6 g, 72% yield).

EXAMPLE 23M(4S)-4-(dibenzylamino)-3-oxo-5-[4-(2-pyridinyl)phenyl]pentanenitrile

A solution of sodium bis(trimethylsilyl) amide (1 M in THF, 50 mL) at−45° C., was treated with a solution of acetonitrile (2.81 mL, 53.4mmol) in THF (10 mL) dropwise and the mixture was stirred for 15 minutesat −45° C. and then cooled to −78° C., treated dropwise with a solutionof the product from Example 23L (7.6 g, 14.8 mmol) in THF (20 mL),stirred at −45° C. for 1 hour, treated with solid NH₄Cl (10 g), warmedto 5° C., followed by the addition of water. The mixture was allowed towarm to 25° C. and was partitioned between ethyl acetate and water. Theorganic phase was washed with brine and dried over MgSO₄, filtered andconcentrated. The residue was titurated with ethanol and the resultingsolid was filtered and dried to give the title compound (4.3 g, 62%yield).

EXAMPLE 23N(2S,4E)-5-amino-2-(dibenzylamino)-6-phenyl-1-[4-(2-pyridinyl)phenyl]-4-hexen-3-one

A solution containing the product from Example 23M (4.3 g, 9.65 mmol) inTHF (15 mL) was treated dropwise with a solution of benzyl magnesiumbromide (30 mL, 1 M in ether) at 0° C., warmed to 25° C., stirred for 16hours, cooled to 0° C., quenched with 10% citric acid, and partitionedbetween ethyl acetate and water. The organic phase was washed with brineand dried over MgSO₄, filtered and concentrated to give the crudeproduct (6.18 g), which was used without further purification.

EXAMPLE 23O(2S,3S,5S)-5-amino-2-(dibenzylamino)-6-phenyl-1-[4-(2-pyridinyl)phenyl]-3-hexanol

(i) A suspension of NaBH₄ (1.75 g, 46.3 mmol) in THF (45 mL) at −10° C.was treated with methanesulfonic acid (7.46 mL, 114.9 mmol) dropwise.After complete addition, a solution containing the product from Example23N (6.18 g, 9.65 mmol) in a mixture of THF (16 mL) and water (1.6 mL)was added and the mixture was stirred at −10° C. for 16 hours.

(ii) A suspension of NaBH₄ (1.75 g, 46.3 mmol) in THF (45 mL) at 0° C.was treated with trifluoroacetic acid (4.4 mL, 57.1 mmol) dropwise,stirred at 0° C. for 30 minutes, treated with a solution of step (i),warmed to 25° C., stirred for 16 hours, treated with a suspension ofNaBH₄ (1.75 g, 46.3 mmol) and trifluoroacetic acid (4.4 mL, 57.1 mmol)prepared as described above at 0° C., warmed to 25° C. and stirred for16 hours. The reaction mixture was cooled to 0° C. and quenchedcautiously by slow addition of NaOH solution (65 mL, 3 N), followed bypartitioning between tert-butyl methyl ether and water. The organicphase was washed with NaOH solution (0.5 N), NH₄Cl solution, and brine,dried over MgSO₄, filtered and concentrated to give the crude product,which was used without further purification.

EXAMPLE 23Ptert-butyl(1S,3S,4S)-1-benzyl-4-(dibenzylamino)-3-hydroxy-5-[4-(2-pyridinyl)phenyl]pentylcarbamate

A solution containing the product from Example 230 (9.65 mmol) intert-butyl methyl ether (50 mL) was treated with 10% K₂CO₃ (23 mL) andditert-butyl dicarbonate (3.5 g, 16.0 mmol) and the mixture was stirredat 25° C. for 1 hour. The reaction mixture was diluted with tert-butylmethyl ether and the organic phase layer was washed with water andbrine, dried over MgSO₄, filtered and concentrated. The residue waschromatographed on silica gel eluting with 0-50% ethyl acetate/hexanesto give the title compound (2.7 g, 43% yield).

EXAMPLE 23Qtert-butyl(1S,3S,4S)-4-amino-1-benzyl-3-hydroxy-5-[4-(2-pyridinyl)phenyl]pentylcarbamate

Method 1 A solution containing the product from Example 23J (0.568 g,0.95 mmol) in a mixture of ethyl acetate (5 mL) and methanol (5 mL) wastreated with Pd(OH)₂ on carbon (0.2 g, 20% Pd by wt.) and HCl solution(0.25 mL, 4N in dioxane), stirred under a hydrogen atmosphere (balloonpressure) for 16 hours at 25° C., filtered through a bed of celite®,rinsed with a mixture of 50% ethyl acetate in methanol, andconcentrated. The residue was partitioned between ethyl acetate andsaturated NaHCO₃. The organic phase was washed with brine and dried overMgSO₄, filtered and concentrated to give the title compound (0.442 g),which was used without further purification.

Method 2 A solution containing the product from Example 23P (2.7 g, 4.21mmol) in a mixture of methanol (20 mL) and ethyl acetate (20 mL) wastreated with 20% Pd(OH)₂ on carbon (1 g) and an HCl solution in dioxane(2 mL, 4 N), stirred under an atmosphere of hydrogen (balloon pressure)for 16 hours at 25° C., heated to 60° C. for 6 hours. The reactioncooled and filtered through celite®, and concentrated. The residue waspartitioned between dichloromethane and half-saturated NaHCO₃. Theorganic phase was dried over MgSO₄, filtered and concentrated to givethe title compound, which was used without further purification.

EXAMPLE 23Rtert-butyl(1S,3S,4S)-1-benzyl-3-hydroxy-4-({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-5-[4-(2-pyridinyl)phenyl]pentylcarbamate

A solution containing the product from Example 23Q (0.442 g, 0.95 mmol)in THF (10 mL) was treated with the product from Example 1F (0.20 g,1.06 mmol), DEPBT (0.45 g, 1.50 mmol), and N,N-diisopropylethylamine(0.85 mL, 4.88 mmol), stirred at 25° C. for 1 hour, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was chromatographed on silica geleluting with 0-75% ethyl acetate/dichloromethane to give the titlecompound (0.34 g, 56% yield).

EXAMPLE 23Smethyl(1S)-1-[({(1S,2S,4S)-4-amino-2-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 23R (0.34 g, 0.54 mmol)in dichloromethane (5 mL) was treated with trifluoroacetic acid (5 mL),stirred at 25° C. for 1 hour, and concentrated. The residue waspartitioned between dichloromethane and saturated NaHCO₃ solution. Theorganic phase was washed with brine, dried over MgSO₄, filtered andconcentrated. The crude product (0.251 g) was used without furtherpurification.

EXAMPLE 23Tmethyl(1S)-1-[({(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 23S (0.075 g, 0.14 mmol)in THF (1.5 mL) was treated with the product from Example 10D (0.073 g,0.21 mmol), DEPBT (0.09 g, 0.30 mmol), and N,N-diisopropylethylamine(0.125 mL, 0.72 mmol), stirred at 25° C. for 16 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The concentrate was purified by reversedphase chromatography on a C18 column eluting with a gradient startingwith 5-100% acetonitrile in water (0.1% TFA). The product waspartitioned between dichloromethane and saturated NaHCO₃ solution. Theorganic phase was washed with brine, dried over MgSO₄, filtered andconcentrated. The residue was then chromatographed on silica gel elutingwith 0-100% ethyl acetate/dichloromethane, followed by 0-10% methanol inethyl acetate, to give the title compound (0.063 g, 54% yield). ¹H NMR(300 MHz, DMSO-d₆), δ ppm 0.83 (s, 9 H), 0.86 (s, 9 H), 1.53 (m, 2 H),2.39 (m, 1 H), 2.45 (m, 3 H), 2.48 (m, 1 H), 2.66 (d, J=10.66 Hz, 1 H),2.78 (d, J=6.99 Hz, 2 H), 2.96 (m, 1 H), 3.07 (q, J=8.70 Hz, 1 H), 3.23(m, 1 H), 3.50 (s, 3 H), 3.62 (m, 1 H), 3.95 (d, J=8.1 Hz, 1H), 3.96 (s,1 H), 4.19 (m, 2 H), 4.34 (m, 2 H), 4.83 (d, J=5.52 Hz, 1 H), 6.79 (d,J=9.56 Hz, 1 H), 7.05 (m, 6 H), 7.15 (d, J=7.35 Hz, 1 H), 7.30 (m, 3 H),7.58 (d, J=9.19 Hz, 1 H), 7.68 (t, J=7.72 Hz, 1 H), 7.86 (m, 5 H), 8.63(d, J=4.78 Hz, 1 H).

EXAMPLE 24 methyl(1S)-1-[({(1S,2S,4S)-1-benzyl-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-[4-(2-pyridinyl)phenyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 24Atert-butyl(1S,2S,4S)-1-benzyl-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-[4-(2-pyridinyl)phenyl]pentylcarbamate

A solution containing the product from Example 2A (0.185 g, 0.37 mmol)in THF (3.5 mL) was treated with the product from Example 10D (0.127 g,0.37 mmol), DEPBT (0.167 g, 0.56 mmol), and N,N-diisopropylethylamine(0.32 mL, 1.84 mmol) and the mixture was stirred at 25° C. for 16 hours.The mixture was partitioned between ethyl acetate and 10% Na₂CO₃solution. The organic phase was washed with additional 10% Na₂CO₃solution and brine, dried over MgSO₄, filtered and concentrated. Theproduct was purified by reversed phase chromatography on a C18 columneluting with 5-100% acetonitrile in water (0.1% TFA). The product waspartitioned between dichloromethane and saturated NaHCO₃ solution. Theorganic phase was washed brine, dried over MgSO₄, filtered andconcentrated. The residue was then chromatographed on silica gel elutingwith 0-10% methanol/chloroform to give the title compound (0.129 g, 46%yield).

EXAMPLE 24Bmethyl(1S)-1-[({(1S,2S,4S)-1-benzyl-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-[4-(2-pyridinyl)phenyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 24A (0.129 g, 0.17 mmol)in dichloromethane (0.8 mL) was treated with trifluoroacetic acid (0.8mL), stirred at 25° C. for 1 hour and concentrated. A solution of theresidue (0.17 mmol) in THF (1.8 mL) was treated with the product fromExample 1F (0.033g, 0.17 mmol), DEPBT (0.077 g, 0.26 mmol), andN,N-diisopropylethylamine (0.30 mL, 1.72 mmol), stirred at 25° C. for 18hours, and partitioned between ethyl acetate and 10% Na₂CO₃ solution.The organic phase was washed with additional 10% Na₂CO₃ solution andbrine, dried over MgSO₄, filtered and concentrated. The residue waschromatographed on silica gel eluting with 0-5% methanol/ethyl acetateto give the title compound (0.057 g, 40% yield). ¹H NMR (300 MHz,DMSO-d₆), δ ppm 0.85 (d, J=1.10 Hz, 18 H), 1.55 (m, 2 H), 2.43 (m, 5 H),2.72 (m, 4 H), 2.95 (m, 1 H), 3.19(m, 1 H), 3.58 (m, 4 H), 3.93 (d,J=9.56 Hz, 1 H), 3.99 (s, 1 H), 4.28 (m, 4 H), 4.84 (d, J=5.52 Hz, 1 H),6.82 (d, J=9.93 Hz, 1 H), 6.97 (d, J=7.72 Hz, 1 H), 7.16 (m, 8 H), 7.29(m, 1 H), 7.52 (d, J=8.82 Hz, 1 H), 7.61 (t, J=7.72 Hz, 1 H), 7.79 (m, 4H), 7.95 (d, J=8.82 Hz, 1 H), 8.61 (d, J=4.78 Hz, 1 H).

EXAMPLE 25methyl(1S,4S,5S,7S,10S)-7-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-4-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate

A solution of the product from Example 23S (0.025 g, 0.047 mmol) in THF(0.5 mL) was treated with the product from Example 1F (0.010g, 0.053mmol), DEPBT (0.020 g, 0.067 mmol), and N,N-diisopropylethylamine (0.040mL, 0.229 mmol), stirred at 25° C. for 16 hours, and partitioned betweenethyl acetate and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with0-100% ethyl acetate/dichloromethane to give the title compound (0.015g, 45% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.77 (s, 9 H), 0.83 (s,9 H), 1.48 (m, 2 H), 2.74 (m, 3 H), 3.50 (s, 3 H), 3.54 (s, 3 H), 3.64(m, 1 H), 3.79 (d, J=9.19 Hz, 1 H), 3.93 (d, J=956 Hz, 1 H), 4.09 (m, 2H), 4.85 (d, J=5.88 Hz, 1 H), 6.60 (d, J=9.93 Hz, 1 H), 6.75 (d, J=9.93Hz, 1 H), 7.11 (m, 5 H), 7.31 (m, 3 H), 7.59 (d, J=9.19 Hz, 1 H), 7.74(d, J=8.82 Hz, 1 H), 7.86 (m, 4 H), 8.63 (d, J=4.41 Hz, 1 H).

EXAMPLE 26 1:1 mixture of (3R,3aS,6aR) and(3S,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-yl(1S,3S,4S)-1-benzyl-3-hydroxy-4-({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-5-[4-(2-pyridinyl)phenyl]pentylcarbamateEXAMPLE 26A 1:1 mixture of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl4-nitrophenyl carbonate and (3S,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-yl4-nitrophenyl carbonate

A solution of (3S,3aR,6aS)- and(3R,3aS,6aR)-3-hydroxy-4H-hexahydrofuro[2,3-b]furan (prepared asdescribed in: Gosh, A. K.; Kincaid, J. F.; Walters, D. E.; Chen, Y.;Chaudhuri, N. C.; Thompson, W. J.; Culberson, C.; Fitzgerald, P. M. D.;Lee. H. Y.; McKee, S. P.; Munson, P. M.; Duong, T. T.; Darke, P. L.;Zugay, J. A.; Schleif, W. A.; Axel, M. G.; Lin, J.; Huff, J. R. Journalof Medicinal Chemistry 1996, 39, 3278-3290.) (1.5 g, 11.5 mmol) indichloromethane (40 mL) at 0° C. was treated with NMM (1.9 mL, 17.3mmol) and 4-nitrophenyl chloroformate (2.9 g, 14.4 mmol), stirred for 16hours at 0° C. and concentrated. The residue was chromatographed onsilica gel, eluting with 25% ethyl acetate in hexanes to give the titlecompound (2.91 g, 86% yield).

EXAMPLE 26B (3R)-hexahydrofuro[2,3-b]furan-3-yl(1S,3S,4S)-1-benzyl-3-hydroxy-4-({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-5-[4-(2-pyridinyl)phenyl]pentylcarbamateand (3R,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-yl(1S,3S,4S)-1-benzyl-3-hydroxy-4-({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-5-[4-(2-pyridinyl)phenyl]pentylcarbamate

A solution of the product from Example 23S (0.05 g, 0.094 mmol) in THF(0.5 mL) was treated with triethylamine (0.025 mL, 0.179 mmol) and theproduct from Example 26A (0.040 g, 0.135 mmol), stirred at 25° C. for 2hours, and partitioned between ethyl acetate and 10% Na₂CO₃ solution.The organic phase was washed with additional 10% Na₂CO₃ solution andbrine, dried over MgSO₄, filtered and concentrated. The residue waschromatographed on silica gel eluting with 0-100% ethylacetate/dichloromethane to give the title compound (0.050 g, 77% yield).¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.86 (d, J=4.78 Hz, 9 H), 1.28 (m, 2H), 1.56 (m, 3 H), 2.62 (m, 2 H), 2.79 (m, 3 H), 3.41 (m, 1 H), 3.51 (s,3 H), 3.58 (m, 1 H), 3.72 (m, 3 H), 3.93 (m, 1 H), 4.18 (m, 1 H), 4.80(m, 2 H), 5.47 (d, J=4.78 Hz, 1 H), 6.84 (t, J=9.93 Hz, 1 H), 7.16 (m, 6H), 7.31 (d, J=8.46 Hz, 3 H), 7.59 (d, J=9.19 Hz, 1 H), 7.89 (m, 4 H),8.63 (d, J=4.78 Hz, 1 H).

EXAMPLE 27 1:1 mixture of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl(1S,2S,4S)-1-benzyl-2-hydroxy-4-({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-5-[4-(2-pyridinyl)phenyl]pentylcarbamateand (3R,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-yl(1S,2S,4S)-1-benzyl-2-hydroxy-4-({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-5-(2-pyridinyl)phenyl]pentylcarbamate

A solution of the product from Example 2C (0.025 g, 0.047 mmol) in THF(0.25 mL) was treated with triethylamine (0.013 mL, 0.093 mmol) and theproduct from Example 26A (0.020 g, 0.067 mmol), stirred at 25° C. for 16hours, and partitioned between ethyl acetate and 10% Na₂CO₃ solution.The organic phase was washed with additional 10% Na₂CO₃ solution andbrine, dried over MgSO₄, filtered and concentrated. The residue waschromatographed on silica gel eluting with 0-100% ethylacetate/dichloromethane to give the title compound (0.024 g, 74% yield).¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.84 (d, J=9.19 Hz, 9 H), 1.44 (m, 5H), 2.73 (m, 5 H), 3.49 (m, 3 H), 3.73 (m, 6 H), 4.19 (m, 1 H), 4.68(dd, J=17.65, 6.25 Hz, 1 H), 4.82 (m, 1 H), 5.49 (m, 1 H), 6.70 (t,J=9.74 Hz, 1 H), 6.86 (t, J=8.82 Hz, 1 H), 7.19 (m, 7 H), 7.31 (m, 1 H),7.88 (m, 5 H), 8.63 (d, J=4.78 Hz, 1 H).

EXAMPLE 28methyl(1S)-1-[({(1S,2S,4S)-2-hydroxy-4-[((2S)-3-methyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 23S (0.025 g, 0.047 mmol)in THF (0.5 mL) was treated with the product from Example 7B (0.025 g,0.060 mmol), DEPBT (0.025 g, 0.084 mmol), and N,N-diisopropylethylamine(0.040 mL, 0.230 mmol), stirred at 25° C. for 2 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was chromatographed on silica geleluting with 0-100% ethyl acetate/dichloromethane, followed by elutingwith 0-10% methanol in ethyl acetate to give the title compound (0.021g, 54% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.60 (d, J=6.62 Hz, 3H), 0.73 (t, J=7.17 Hz, 3 H), 0.87(m, 10 H), 1.27 (m, 1 H), 1.54 (m, 2H), 1.75 (m, 1 H), 2.43 (m, 4 H), 2.66 (m, 1 H), 2.77 (d, J=6.99 Hz, 2H), 2.91 (m, 1 H), 3.12 (m, 3 H), 3.51 (s, 3 H), 3.59 (m, 1 H), 3.85 (d,J=11.03 Hz, 1 H), 3.94 (d, J=9.56 Hz, 1 H), 4.14 (m, 2 H), 4.33 (s, 2H), 4.81 (d, J=5.15 Hz, 1 H), 6.80 (d, J=9.56 Hz, 1 H), 7.07 (m, 7 H),7.30 (d, J=7.72 Hz, 3 H), 7.58 (d, J=8.82 Hz, 1 H), 7.65 (t, J=7.54 Hz,1 H), 7.87 (m, 5 H), 8.63 (d, J=4.04 Hz, 1 H).

EXAMPLE 29methyl(1S)-1-[({(1R,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 1H (0.176 g, 0.33 mmol)in THF (3.3 mL) was treated with the product from Example 10D (0.113 g,0.33 mmol), DEPBT (0.148 g, 0.49 mmol), and N,N-diisopropylethylamine(0.29 mL, 1.66 mmol), stirred at 25° C. for 16 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was purified by reversed phasechromatography on a C18 column eluting with a gradient starting with5-100% acetonitrile in water (0.1% TFA). The product was partitionedbetween ethyl acetate and saturated NaHCO₃, and the organic phase waswashed with brine and dried over MgSO₄, filtered and concentrated togive the title compound (0.176 g, 65% Meld). ¹H NMR (300 MHz, DMSO-d₆),δ ppm 0.80 (s, 9 H), 0.88 (s, 9 H), 1.29 (m, 2 H), 1.53 (m, 1 H), 2.45(s, 3 H), 2.66 (m, 3 H), 2.83 (dd, J=13.79, 6.07 Hz, 1 H), 3.03 (m, 2H), 3.23 (m, 1 H), 3.53 (m, 4 H), 3.84 (d, J=9.56 Hz, 1 H), 4.01 (m, 2H), 4.16 (m, 1 H), 4.34 (m, 2 H), 4.44 (d, J=6.99 Hz, 1 H), 6.88 (d,J=9.56 Hz, 1 H), 7.09 (m, 7 H), 7.24 (d, J=8.09 Hz, 2 H), 7.32 (m, 1 H),7.54 (d, J=9.56 Hz, 1 H), 7.67 (t, J=7.72 Hz, 1 H), 7.89 (m, 5 H), 8.64(d, J=4.04 Hz, 1 H).

EXAMPLE 30methyl(1R,4S,5S,7S,10S)-4-benzyl-10-tert-butyl-5-hydroxy-1-[1-methyl-1-(methylsulfanyl)ethyl]-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamateEXAMPLE 30A(2R)-2-[(methoxycarbonyl)amino]-3-methyl-3-(methylsulfanyl)butanoic acid

A solution of L-penicillamine (0.5 g, 3.35 mmol) in methanol (3.3 mL) at0° C. was treated with aqueous NaOH solution (3.7 mL, 1 N) and methyliodide (0.23 mL, 3.69 mmol), stirred at 0° C. for 16 hours, treated withadditional aqueous NaOH solution (3.5 mL, 3 N) at 0° C., followed bymethyl chloroformate (0.5 mL, 6.47 mmol), warmed to 25° C. and stirredfor 3 hours, and partitioned between ethyl acetate and water. Theorganic phase was washed with brine and dried over MgSO₄, filtered andconcentrated to give the title compound (0.428 g, 58% yield), which wasused without further purification.

EXAMPLE 30Bmethyl(1R,4S,5S,7S,10S)-4-benzyl-10-tert-butyl-5-hydroxy-1-[1-methyl-1-(methylsulfanyl)ethyl]-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate

A solution containing the product from Example 2C (0.10 g, 0.18 mmol) inTHF (2 mL) was treated with the product from Example 30A (0.05 g, 0.226mmol), DEPBT (0.085 g, 0.28 mmol), and N,N-diisopropylethylamine (0.165mL, 0.947 mmol), stirred at 25° C. for 1 hour, and partitioned betweenethyl acetate and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with0-100% ethyl acetate/dichloromethane to give the title compound (0.052g, 38% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.80 (s, 9 H), 1.10 (s,3 H), 1.21 (s, 3 H), 1.54 (m, 2 H), 1.98 (s, 3 H), 2.57 (m, 1 H), 2.75(m, 3 H), 3.49 (s, 3 H), 3.56 (s, 3 H), 3.64 (m, 1 H), 3.82 (d, J=9.56Hz, 1 H), 4.17 (m, 3 H), 4.83 (d, J=5.88 Hz, 1 H), 6.61 (d, J=9.56 Hz, 1H), 6.90 (d, J=9.56 Hz, 1 H), 7.15 (m, 7 H), 7.31 (m, 1 H), 7.84 (m, 6H), 8.63 (d, J=4.78 Hz, 1 H).

EXAMPLE 31methyl(1R,4S,5S,7S,10S)-4-benzyl-10-tert-butyl-5-hydroxy-1-[1-methyl-1-(methylsulfonyl)ethyl]-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate

A solution of the product from Example 30B (0.015 g, 0.020 mmol) in amixture of acetone and water (3:1, respectively, 0.20 mL) and THF (0.10mL) was treated with 4-methylmorpholine N-oxide (0.014 g, 0.120 mmol)and aqueous OSO₄ solution (0.033 mL, 4%), stirred at 25° C. for 16hours, and partitioned between ethyl acetate and water. The organicphase was washed with brine and dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with0-100% ethyl acetate/dichloromethane to give the title compound (0.013g, 83% yield). H NMR (300 MHz, DMSO-d₆), δ ppm 0.82 (s, 9 H), 1.14 (s, 3H), 1.26 (s, 3 H), 1.50 (m, 2 H), 2.57 (m, 1 H), 2.75 (m, 3 H), 2.88 (s,3 H), 3.50 (s, 3 H), 3.57 (s, 3 H), 3.69 (m, 1 H), 3.83 (d, J=10.30 Hz,1 H), 4.03 (m, 1 H), 4.16 (m, 1 H), 4.69 (d, J=10.30 Hz, 1 H), 4.89 (d,J=5.52 Hz, 1 H), 6.64 (d, J=9.56 Hz, 1 H), 7.16 (m, 8 H), 7.31 (m, 1 H),7.85 (m, 5 H), 8.01 (d, J=9.19 Hz, 1 H), 8.63 (d, J=4.41 Hz, 1 H).

EXAMPLE 32methyl(1R,4S,6S,7S,10S)-4-benzyl-10-tert-butyl-6-hydroxy-1-[1-methyl-1-(methylsulfanyl)ethyl]-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate

A solution containing the product from Example 23S (0.025 g, 0.047 mmol)in THF (0.5 mL) was treated with the product from Example 30A (0.0125 g,0.056 mmol), DEPBT (0.021 g, 0.070 mmol), and N,N-diisopropylethylamine(0.040 mL, 0.230 mmol), stirred at 25° C. for 16 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was chromatographed on silica geleluting with 0-100% ethyl acetate/dichloromethane to give the titlecompound (0.024 g, 69% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.84 (s,9 H), 1.08 (s, 3 H), 1.11 (s, 3 H), 1.50 (m, 2 H), 1.93 (s, 3 H), 2.45(m, 1 H), 2.75 (m, 3 H), 3.51 (s, 3 H), 3.56 (s, 3 H), 3.67 (m, 1 H),394 (d, J=9.5 Hz, 1 H), 4.10 (d, J=10.30 Hz, 3 H), 4.84 (d, J=5.88 Hz, 1H), 6.79 (dd, J=15.81, 9.93 Hz, 2 H), 7.09 (m, 5 H), 7.30 (d, J=7.35 Hz,3 H), 7.57 (s, 1 H), 7.87 (m, 5 H), 8.63 (d, J=4.41 Hz, 1 H).

EXAMPLE 33methyl(1R,4S,6S,7S,10S)-4-benzyl-10-tert-butyl-6-hydroxy-1-[1-methyl-1-(methylsulfonyl)ethyl]-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate

A solution of the product from Example 32 (0.015 g, 0.020 mmol) in amixture of acetone and water (3:1, respectively, 0.20 mL) and THF (0.15mL) was treated with 4-methylmorpholine N-oxide (0.014 g, 0.120 mmol)and aqueous OSO₄ solution (0.030 mL, 4%), stirred at 25° C. for 16hours, and partitioned between ethyl acetate and water. The organicphase was washed with brine and dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with0-100% ethyl acetate/dichloromethane, followed by 0-5% methanol in ethylacetate, to give the title compound (0.012 g, 77% yield). ¹H NMR (300MHz, DMSO-d₆), δ ppm 0.85 (s, 9 H), 1.05 (s, 3 H), 1.25 (s, 3 H), 1.50(m, 2 H), 2.79 (m, 8 H), 3.51 (s, 3 H), 3.56 (s, 3 H), 3.95 (d, J=9.19Hz, 1 H), 4.08 (m, 2 H), 4.53 (d, J=10.30 Hz, 1 H), 4.88 (d, J=5.88 Hz,1 H), 6.79 (d, J=9.93 Hz, 1 H), 7.11 (m, 6 H), 7.31 (m, 3 H), 7.62 (d,J=9.56 Hz, 1 H), 7.86 (m, 4 H), 8.17 (d, J=8.82 Hz, 1 H), 8.63 (d,J=4.41 Hz, 1 H).

EXAMPLE 34methyl(1S)-1-[({(1S,3S,4S)-4-{[(2S)-3,3-dimethyl-2-(2-oxo-3-{[2-(3-pyridinyl)-1,3-thiazol-4-yl]methyl}-1-imidazolidinyl)butanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 2C (0.025 g, 0.047 mmol)in THF (0.5 mL) was treated with the product from Example 19D (0.030 g,0.061 mmol), DEPBT (0.020 g, 0.067 mmol), and N,N-diisopropylethylamine(0.040 mL, 0.230 mmol), stirred at 25° C. for 16 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was chromatographed on silica geleluting with 0-100% ethyl acetate/dichloromethane, followed by 0-5%methanol in ethyl acetate, to give the title compound (0.029 g, 70%yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.83 (s, 9 H), 0.89 (s, 9 H),1.54 (m, 2 H), 2.34 (m, 1 H), 2.63 (m, 2 H), 2.79 (m, 1 H), 3.16 (m, 4H), 3.50 (s, 3 H), 3.65 (m, 1 H), 3.85 (d, J=9.93 Hz, 1 H), 4.14 (m, 3H), 4.50 (m, 3 H), 6.63 (d, J=9.56 Hz, 1 H), 6.98 (m, 1 H), 7.06 (m, 4H), 7.22 (d, J=8.09 Hz, 2 H), 7.31 (m, 1 H), 7.52 (m, 2 H), 7.61 (s, 1H), 7.87 (m, 5 H), 8.31 (m, 1 H), 8.65 (m, 2 H), 9.14 (d, J=1.84 Hz, 1H).

EXAMPLE 35methyl(1S)-1-[({(1S,2S,4S)-4-{[(2S)-3,3-dimethyl-2-(2-oxo-3-{[2-(3-pyridinyl)-1,3-thiazol-4-yl]methyl}-1-imidazolidinyl)butanoyl]amino}-2-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 23S (0.025 g, 0.047 mmol)in THF (0.5 mL) was treated with the product from Example 19D (0.030 g,0.061 mmol), DEPBT (0.020 g, 0.067 mmol), and N,N-diisopropylethylamine(0.040 mL, 0.230 mmol), stirred at 25° C. for 16 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was chromatographed on silica geleluting with 0-100% ethyl acetate/dichloromethane, followed by 0-5%methanol in ethyl acetate, to give the title compound (0.021 g, 50%yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.82 (s, 9 H), 0.86 (s, 9 H),1.53 (m, 2 H), 2.40 (m, 1 H), 2.64 (d, J=13.97 Hz, 1 H), 2.77 (d, J=6.62Hz, 2 H), 3.15 (m, 4 H), 3.51 (s, 3 H), 3.62 (m, 1 H), 3.96 (m, 2 H),4.18 (m, 2 H), 4.47 (m, 2 H), 4.82 (d, J=5.52 Hz, 1 H), 6.79 (d, J=9.56Hz, 1 H), 6.95 (m, 1 H), 7.03 (m, 4 H), 7.30 (m, 3 H), 7.54 (m, 3 H),7.87 (m, 5 H), 8.30 (m, 1 H), 8.65 (m, 2 H), 9.14 (d, J=1.47 Hz, 1 H).

EXAMPLE 36methyl(1S)-1-[({(1S,3S,4S)-3-hydroxy-4-[((2S)-3-methyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2,4-dioxo-1-imidazolidinyl}pentanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 36Atert-butyl(2S,3S)-2-[(2-ethoxy-2-oxoethyl)amino]-3-methylpentanoate

A solution of L-iso-leucine tert-butyl ester hydrochloride (5 g, 22.34mmol) in DMF (30 mL) was treated with triethylamine (3.1 mL, 22.34mmol), stirred for 1 hour at 25° C., filtered to remove solid salts, andthe filtrate was treated with triethylamine (9.3 mL, 67.0 mmol) andethyl bromoacetate (9.9 mL, 67.0 mmol), and the reaction was stirred for3 hours at 25° C. The reaction mixture was partitioned between ethylacetate and water, and the organic phase was washed with brine and driedover MgSO₄, filtered and concentrated to give the title compound (5.7 g,93% yield), which was used without further purification.

EXAMPLE 36Btert-butyl(2S,3S)-2-[(aminocarbonyl)(2-ethoxy-2-oxoethyl)amino]-3-methylpentanoate

A solution containing the product from Example 36A (5.7 g, 20.9 mmol) indichloromethane (60 mL) at 0° C. was treated with chlorosulfonylisocyanate (2.7 mL, 31.0 mmol) and the mixture was stirred at 0° C. for16 hours. Water (60 mL) was added to the cold reaction and the mixturewas warmed to 25° C. and stirred for 4 hours. The reaction waspartitioned between dichloromethane and water, and the organic phase waswashed with brine and dried over MgSO₄, filtered and concentrated togive the title compound (6.83 g), which was used without furtherpurification.

EXAMPLE 36Ctert-butyl(2S,3S)-2-(2,4dioxo-1-imidazolidinyl)-3-methylpentanoate

A solution containing the product from Example 36B (6.8 g, 20.9 mmol) inmethanol (30 mL) was treated with triethylamine (5.6 mL, 40.2 mmol),stirred at 50° C. for 2 hours, and concentrated. The residue waschromatographed on silica gel eluting with 0-30% ethylacetate/dichloromethane to give the title compound (2.53 g, 47% yield).

EXAMPLE 36Dtert-butyl(2S,3S)-3-methyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2,4dioxo-1-imidazolidinyl}pentanoate

A solution containing the product from Example 36C (0.107 g, 0.396 mmol)in dichloromethane (2 mL) at 0° C. was treated with6-methyl-2-pyridinemethanol (0.053 g, 0.435 mmol), triphenylphosphine(0.135 g, 0.515 mmol), followed by diethyl azodicarboxylate (0.080 mL,0.515 mmol), stirred at 25° C. for 16 hours. Water (2 mL) was added andthe reaction was stirred for 2 hours at 25° C. The reaction mixture waspartitioned between dichloromethane and water, and the organic phase waswashed with brine and dried over MgSO₄, filtered and concentrated. Theresidue was chromatographed on silica gel eluting with 0-30% ethylacetate/dichloromethane to give the title compound (0.154 g, 94% yield).

EXAMPLE 36E(2S,3S)-3-methyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2,4-dioxo-1-imidazolidinyl}pentanoicacid

A solution containing the product from Example 36D (0.154 g, 0.410 mmol)in dichloromethane (3 mL) was treated with trifluoracetic acid (3 mL),stirred at 25° C. for 16 hours and concentrated. The residue waspurified by reversed phase chromatography on a C18 column eluting with agradient starting with 5-100% acetonitrile in water (0.1% TFA) to givethe title compound (0.153 g) as the trifluoroacetic acid salt.

EXAMPLE 36Fmethyl(1S)-1-[({(1S,3S,4S)-3-hydroxy-4-[((2S)-3-methyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2,4-dioxo-1-imidazolidinyl}pentanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 2C (0.025 g, 0.047 mmol)in THF (0.5 mL) was treated with the product from Example 36E (0.020 g,0.061 mmol), DEPBT (0.021 g, 0.071 mmol), and N,N-diisopropylethylamine(0.041 mL, 0.235 mmol), stirred at 25° C. for 2 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was chromatographed on silica geleluting with 0-100% ethyl acetate/dichloromethane, followed by 0-10%methanol in ethyl acetate, to give the title compound (0.026 g, 68%yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.76 (m, 18 H), 1.16 (m, 1 H),1.29 (m, 1 H), 1.52 (m, 1 H), 1.76 (s, 1 H), 2.39 (s, 3 H), 2.68 (m, 4H), 3.20 (m, 2 H), 3.50 (s, 3 H), 3.83 (m, 2 H), 4.13 (m, 2 H), 4.67 (m,2 H), 6.66 (d, J=9.56 Hz, 1 H), 7.07 (m, 7 H), 7.22 (d, J=8.09 Hz, 2 H),7.31 (m, 1 H), 7.66 (t, J=7.72 Hz, 1 H), 7.86 (m, 6 H), 8.63 (d, J=4.04Hz, 1 H).

EXAMPLE 37methyl(1S)-1-[({(1S,2S,4S)-2-hydroxy-4-[((2S)-3-methyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2,4-dioxo-1-imidazolidinyl}pentanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 23S (0.025 g, 0.047 mmol)in THF (0.5 mL) was treated with the product from Example 36E (0.020 g,0.061 mmol), DEPBT (0.021 g, 0.071 mmol), and N,N-diisopropylethylamine(0.041 mL, 0.235 mmol), stirred at 25° C. for 2 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was chromatographed on silica geleluting with 0-100% ethyl acetate/dichloromethane, followed by 0-10%methanol in ethyl acetate, to give the title compound (0.025 g, 64%yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.57 (d, J=6.62 Hz, 3 H), 0.71(t, J=7.17 Hz, 3 H), 0.82 (m, 12 H), 1.26 (m, 1 H), 1.54 (m, 2 H), 1.73(m, 1 H), 2.33 (m, 4 H), 2.76 (m, 3 H), 3.51 (s, 3 H), 3.59 (m, 1 H),3.82 (d, J=18.38 Hz, 1 H), 4.01 (m, 2 H), 4.18 (s, 1 H), 4.67 (m, 2 H),4.87 (d, J=5.15 Hz, 1 H), 6.82 (d, J=9.56 Hz, 1 H), 7.02 (m, 6 H), 7.12(d, J=7.72 Hz, 1 H), 7.30 (d, J=8.46 Hz, 3 H), 7.64 (m, 2 H), 7.87 (m, 4H), 8.09 (d, J=9.19 Hz, 1 H), 8.63 (d, J=4.04 Hz, 1 H).

EXAMPLE 38methyl(1S)-1-[({(1S,3S,4S)-4-{[(2,6-dimethylphenoxy)acetyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 2C (0.020 g, 0.038 mmol)in THF (0.4 mL) was treated with 2,6-dimethylphenoxy acetic acid (U.S.Pat. No. 5,914,332, see Example 1H) (0.008 g, 0.044 mmol), DEPBT (0.017g, 0.057 mmol), and N,N-diisopropylethylamine (0.030 mL, 0.172 mmol),stirred at 25° C. for 16 hours. The mixture was partitioned betweenethyl acetate and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with0-80% ethyl acetate/chloroform to give the title compound (0.021 g, 77%yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.83 (s, 9 H), 1.52 (m, 2 H),2.08 (s, 6 H), 2.72 (m, 2 H), 2.80 (m, 2 H), 3.51 (s, 3 H), 3.72 (m, 1H), 3.85 (d, J=9.19 Hz, 1 H), 4.01 (s, 2 H), 4.22 (m, 2 H), 5.05 (d,J=5.88 Hz, 1 H), 6.71 (d, J=9.93 Hz, 1 H), 6.92(m, 3 H), 7.26 (m, 8 H),7.45 (d, J=9.56 Hz, 1 H), 7.85 (m, 5 H), 8.62 (d, J=4.78 Hz, 1 H).

EXAMPLE 39methyl(1S)-1-[({(1S,2S,4S)-4-{[(2,6-dimethylphenoxy)acetyl]amino}-2-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 23S (0.020 g, 0.038 mmol)in THF (0.4 mL) was treated with 2,6-dimethylphenoxy acetic acid (U.S.Pat. No. 5,914,332, see Example 1H) (0.008 g, 0.044 mmol), DEPBT (0.017g, 0.057 mmol), and N,N-diisopropylethylamine (0.030 mL, 0.172 mmol),stirred at 25° C. for 16 hours, and partitioned between ethyl acetateand 10% Na₂CO₃ solution. The organic phase was washed with additional10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with0-80% ethyl acetate/chloroform to give the title compound (0.016 g, 61%yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.86 (s, 9 H), 1.63 (m, 2 H),2.07 (s, 6 H), 2.78 (m, 4 H), 3.51 (s, 3 H), 3.62 (m, 1 H), 3.94 (m, 3H), 4.25 (m, 2 H), 4.87 (d, J=5.15 Hz, 1 H), 6.89 (m, 4 H), 7.19 (m, 5H), 7.31 (m, 3 H), 7.61 (d, *8.46 Hz, 1 H), 7.84 (m, 5 H), 8.62 (d,J=4.41 Hz, 1 H).

EXAMPLE 40methyl(1S)-1-[({(1S,3S,4S)-3-hydroxy-4-({(2S)-2-[3-(imidazo[1,5-a]pyridin-3-ylmethyl)-2-oxo-1-imidazolidinyl]-3,3-dimethylbutanoyl}amino)-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 40A imidazo[1,5-a]pyridine-3-carbaldehyde

To imidazo[1,5-a]pyridine (2.337 g, 19.78 mmol) in tetrahydrofuran (40mL) was added n-butyl lithium (2.5 M in hexane, 15.76 mL, 39.4 mmol) at−40° C. The mixture was stirred at −40° C. for 3.5 hours, followed bythe addition of dimethylformamide (3.1 mL, 40 mmol). The reactionmixture was stirred at 25° C. overnight and quenched with water. Themixture was then partitioned between dichloromethane (80 mL) and water(15 mL). The organic phase layer was dried with anhydrous sodiumsulfate, filtered and concentrated in vacuo. The crude material waspurified by chromatography eluting with 0-50% ethylacetate/dichloromethane to give the title compound (1.78 g, 62% yield).

EXAMPLE 40B tert-butyl(2S)-2-[3-(imidazo[1,5-a]pyridin-3-ylmethyl)-2-oxo-1-imidazolidinyl]-3,3-dimethylbutanoate

A solution of the product from Example 40A (1.809 g, 12.38 mmol) and theproduct from Example 6F (2.85 g, 12.38 mmol) in ethanol (35 mL) andbenzene (35 mL) was treated with molecular sieves (3 Å, 1.5 g). Themixture was stirred at 60° C. overnight and cooled to 25° C. To thereaction mixture was added sodium borohydride (1.407 g, 37.19 mmol) andthen stirred for 3 hours at 25° C. The reaction mixture was quenchedwith an aqueous solution of saturated ammonium chloride at 0° C. Themixture was partitioned between water (50 mL) and ethyl acetate (100mL). The organic phase layer was separated and washed with water andbrine, dried with anhydrous sodium sulfate, filtered and concentrated.The residue was treated with 1,2-dichloroethane (247 mL),N,N-diisopropylethylamine (2.2 mL, 12.63 mmol) and N,N′-disuccinimidylcarbonate (3.823 g, 14.92 mmol). The solution was stirred at 25° C.overnight and then washed with a solution of 10% sodium carbonate (3×50mL) and water (50 mL). The organic phase layer was dried with anhydroussodium sulfate, filtered and concentrated in vacuo The crude materialwas purified by chromatography eluting with 0-100% ethylacetate/dichloromethane to give the title compound (3 g, 63% yield).

EXAMPLE 40C(2S)-2-[3-(imidazo[1,5-a]pyridin-3-ylmethyl)-2-oxo-1-imidazolidinyl]-3,3-dimethylbutanoicacid

A solution containing the product from Example 40B (0.039 g, 0.096 mmol)in dichloromethane (0.5 mL) was treated with trifluoracetic acid (0.5mL), and the mixture was stirred at 25° C. for 2 hours. The solvent wasconcentrated and azeotroped with toluene to give the title compound asthe trifluoroacetic acid salt, which was used without furtherpurification.

EXAMPLE 40Dmethyl(1S)-1-[({(1S,3S,4S)-3-hydroxy-4-({(2S)-2-[3-(imidazo[1,5-a]pyridin-3-ylmethyl)-2-oxo-1-imidazolidinyl]-3,3-dimethylbutanoyl}amino)-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 2C (0.021 g, 0.048 mmol)in THF (0.5 mL) was treated with the product from Example 40C (0.020 g;0.061 mmol), DEPBT (0.021 g, 0.071 mmol), and N,N-diisopropylethylamine(0.042 mL, 0.235 mmol), stirred at 25° C. for 16 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was purified by reversed phasechromatography on a C18 column eluting with 5-100% acetonitrile in water(0.1% TFA). The reaction was partitioned between ethyl acetate andsaturated NaHCO₃, and the organic phase was washed with brine and driedover MgSO₄, filtered and concentrated to give the title compound (0.018g, 42% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.83 (s, 9 H), 0.86 (s,9 H), 1.26 (m, 1 H), 1.53 (m, 2 H), 2.58 (m, 3 H), 2.77 (m, 2 H), 3.03(m, 2 H), 3.50 (s, 3 H), 3.65 (m, 1 H), 3.84 (d, J=9.93 Hz, 1 H), 4.13(m, 3 H), 4.52 (m, 2 H), 4.92 (d, 15.44 Hz, 1 H), 6.64 (t, J=7.54 Hz, 3H), 6.71 (m, 1 H), 6.83 (m, 4 H), 7.22 (d, J=8.09 Hz, 2 H), 7.31 (m, 1H), 7.41 (m, 2 H), 7.59 (d, J=9.19 Hz, 1 H), 7.86 (m, 5 H), 8.35 (d,J=7.35 Hz, 1 H), 8.63 (d, J=4.78 Hz, 1 H).

EXAMPLE 41methyl(1S)-1-[({(1S,2S,4S)-2-hydroxy-4-({(2S)-2-[3-(imidazo[1,5-a]pyridin-3-ylmethyl)-2-oxo-1-imidazolidinyl]-3,3-dimethylbutanoyl}amino)-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 23S (0.021 g, 0.048 mmol)in THF (0.5 mL) was treated with the product from Example 40C (0.020 g,0.061 mmol), DEPBT (0.021 g, 0.071 mmol), and N,N-diisopropylethylamine(0.042 mL, 0.235 mmol), stirred at 25° C. for 16 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was purified by reversed phasechromatography on a C18 column eluting with 5-100% acetonitrile in water(0.1% TFA). The reaction was partitioned between ethyl acetate andsaturated NaHCO₃, and the organic phase was washed with brine and driedover MgSO₄, filtered and concentrated to give the title compound (0.019g, 47% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.79 (s, 9 H), 0.86 (s,9 H), 1.28 (m, 1 H), 1.51 (m, 2 H), 2.09 (m, 1 H), 2.26 (m, 1 H), 2.80(m, 3 H), 2.97 (m, 1 H), 3.09 (m, 1 H), 3.50 (s, 3 H), 3.61 (m, 1 H),3.95 (m, 2 H), 4.16 (m, 2 H), 4.52 (d, J=15.44 Hz, 1 H), 4.85 (m, 2 H),6.65 (m, 3 H), 6.78 (m, 3 H), 6.87 (d, J=6.99 Hz, 2 H), 7.30 (m, 3 H),7.38 (s, 1 H), 7.58 (d, J=9.19 Hz, 2 H), 7.85 (m, 5 H), 8.33 (d, J=6.99Hz, 1 H), 8.63 (d, J=4.41 Hz, 1 H).

EXAMPLE 42methyl(1S)-1-[({(1S,3S,4S)-4-({(2S)-3,3-dimethyl-2-[2-oxo-3-(4-quinolinylmethyl)-1-imidazolidinyl]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 42Atert-butyl(2S)-3,3-dimethyl-2-[2-oxo-3-(4-quinolinylmethyl)-1-imidazolidinyl]butanoate

A solution containing the product from Example 6F (0.367 g, 1.59 mmol)in a mixture of benzene (5 mL) and methanol (5 mL) was treated with4-quinolinecarboxaldehyde (0.25 g, 1.59 mmol), heated at 50° C. for 3hours, cooled to 25° C. and treated with sodium borohydride (0.12 g,3.18 mmol), stirred at 25° C. for 2 hours, quenched with sodiumbicarbonate solution and partitioned between ethyl acetate and water.The organic phase was washed with brine and dried over MgSO₄, filteredand concentrated. A solution of the concentrate (1.59 mmol) in toluene(10 mL) was treated with bis(4-nitrophenyl) carbonate (0.58 g, 1.9mmol), heated at 100° C. for 16 hours, cooled and partitioned betweenethyl acetate and saturated Na₂CO₃. The organic phase was washed withbrine and dried over MgSO₄, filtered and concentrated. The residue waschromatographed on silica gel eluting with 0-20% acetone/dichloromethaneto give the title compound (0.355 g, 57% yield).

EXAMPLE 42B(2S)-3,3-dimethyl-2-[2-oxo-3-(4-quinolinylmethyl)-1-imidazolidinyl]butanoicacid

A solution containing the product from Example 42A (0.355 g, 0.89 mmol)in dichloromethane (4 mL) was treated with trifluoracetic acid (4 mL),and the mixture was stirred at 25° C. for 2 hours. The solvent wasconcentrated and azeotroped with toluene several times to give the crudeproduct as the trifluoroacetic acid salt, which was used without furtherpurification.

EXAMPLE 42Cmethyl(1S)-1-[({(1S,3S,4S)-4-({(2S)-3,3-dimethyl-2-[2-oxo-3-(quinolinylmethyl)-1-imidazolidinyl]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 2C (0.025 g, 0.047 mmol)in THF (0.5 mL) was treated with the product from Example 42B (0.024 g,0.070 mmol), DEPBT (0.021 g, 0.070 mmol), and N,N-diisopropylethylamine(0.041 mL, 0.235 mmol) and the mixture was stirred at 25° C. for 2hours. The mixture was partitioned between ethyl acetate and 10% Na₂CO₃solution. The organic phase was washed with additional 10% Na₂CO₃solution and brine, dried over MgSO₄, filtered and concentrated. Theresidue was chromatographed on silica gel eluting with 0-100% ethylacetate/dichloromethane, followed by 0-5% methanol in ethyl acetate, togive the title compound (0.027 g, 67% yield). ¹H NMR (500 MHz, DMSO-d₆),δppm 0.82(s, 9H), 0.89(s, 9H), 1.55 (m, 2H), 2.27(m, 1H), 2.65-2.60(m,3H), 2.77(m, 1H), 2.85(m, 1H), 3.03(m, 1 H), 3.17(m, 1H), 3.49(s, 3H),3.65(m, 1H), 3.84(d, J=8.79 Hz, 1H), 4.08(d, J=33.69 Hz, 3H), 4.52(d,J=7.81 Hz, 1H), 4.79(dd, J=152.34, 15.63 Hz, 2H), 6.57(d, J=8.79 Hz,1H), 6.81(t, J=7.32 Hz, 2H), 6.90(t, J=7.08 Hz, 1H), 6.96(d, J=6.84 Hz,2H), 7.22(d, J=7.81 Hz, 2H), 7.29(m, 1H), 7.46-7.42(m, 2H), 7.63(t,J=7.57 Hz, 1H), 7.90-7.76(m, 5H), 8.06(d, J=7.81 Hz, 1H), 8.31(d, J=8.30Hz, 1H), 8.62(d, J=3.91 Hz, 1H), 8.90(d, J=4.39 Hz, 1H).

EXAMPLE 43methyl(1S)-1-[({(1S,2S,4S)-4-({(2S)-3,3-dimethyl-2-[2-oxo-3-(4-quinolinylmethyl)-1-imidazolidinyl]butanoyl}amino)-2-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 23S (0.025 g, 0.047 mmol)in THF (0.5 mL) was treated with the product from Example 42B (0.024 g,0.070 mmol), DEPBT (0.021 g, 0.070 mmol), and N,N-diisopropylethylamine(0.041 mL, 0.235 mmol) and the mixture was stirred at 25° C. for 2hours. The mixture was partitioned between ethyl acetate and 10% Na₂CO₃solution. The organic phase was washed with additional 10% Na₂CO₃solution and brine, dried over MgSO₄, filtered and concentrated. Theresidue was chromatographed on silica gel eluting with 0-100% ethylacetate/dichloromethane, followed by 0-5% methanol in ethyl acetate, togive the title compound (0.015 g, 37% yield). ¹H NMR (500 MHz, DMSO-d₆),δ ppm 0.83(s, 9H), 0.85(s, 9H), 1.61-1.50(m, 2H), 2.41-2.31(m, 2H),2.69-2.59(m, 1H), 2.78(bs, 2H), 2.88(m, 1H), 3.03-2.95(m, 1H),3.23-3.14(m, 1H), 3.50(s, 3H), 3.61(m, 1H), 3.94(m, 1H), 4.00(s, 1H),4.18(m, 2H), 4.81(bs, 1H), 4.92-4.64(dd, J=15.63, 126.95 Hz, 2H),6.87-6.73(m, 4H), 6.96(m, 2H), 7.29(m, 3 H), 7.41(bs, 1H), 7.61-7.54(m,2H), 7.89-7.77(m, 5H), 8.05(d, J=7.81 Hz, 1H), 8.29(d, J=7.32 Hz, 1H),8.62(bs, 1H), 8.89(bs, 1H).

EXAMPLE 44methyl(1S)-1-[({(1S,2S,4S)-2-hydroxy-4-{[(2S)-2-(3-{[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 23S (0.025 g, 0.047 mmol)in THF (0.5 mL) was treated with the product from Example 17F (0.030 g,0.066 mmol), DEPBT (0.021 g, 0.070 mmol), and N,N-diisopropylethylamine(0.041 mL, 0.235 mmol) and the mixture was stirred at 25° C. for 2hours. The mixture was partitioned between ethyl acetate and 10% Na₂CO₃solution. The organic phase was washed with additional 10% Na₂CO₃solution and brine, dried over MgSO₄, filtered and concentrated. Theresidue was chromatographed on silica gel eluting with 0-100% ethylacetate/dichloromethane, followed by 0-5% methanol in ethyl acetate, togive the title compound (0.026 g, 64% yield). ¹H NMR (300 MHz, DMSO-d₆),δ ppm 0.82 (s, 9 H), 0.86 (s, 9 H), 1.42 (d, J=4.78 Hz, 6 H), 1.55 (m, 2H), 2.39 (m, 2 H), 2.65 (d, J=13.24 Hz, 1 H), 2.78 (d, J=6.25 Hz, 2 H),2.98 (m, 1 H), 3.20 (m, 3 H), 3.51 (s, 3 H), 3.61 (m, 1 H), 3.98 (m, 2H), 4.19 (m, 2 H), 4.39 (m, 2 H), 4.82 (d, J=5.52 Hz, 1 H), 6.78 (d,J=9.19 Hz, 1 H), 7.06 (m, 6 H), 7.31 (m, 3 H), 7.55 (m, 2 H), 7.76 (t,J=7.72 Hz, 1 H), 7.86 (m, 5 H), 8.63 (d, J=4.04 Hz, 1 H).

EXAMPLE 45methyl(1S)-1-[({(1S,3S,4S)-3-hydroxy-4-{[(2S)-2-(3-{[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 2C (0.025 g, 0.047 mmol)in THF (0.5 mL) was treated with the product from Example 17F (0.030 g,0.066 mmol), DEPBT (0.021 g, 0.070 mmol), and N,N-diisopropylethylamine(0.041 mL, 0.235 mmol) and the mixture was stirred at 25° C. for 2hours. The mixture was partitioned between ethyl acetate and 10% Na₂CO₃solution. The organic phase was washed with additional 10% Na₂CO₃solution and brine, dried over MgSO₄, filtered and concentrated. Theresidue was chromatographed on silica gel eluting with 0-100% ethylacetate/dichloromethane, followed by 0-5% methanol in ethyl acetate, togive the title compound (0.035 g, 86% yield). ¹H NMR (300 MHz, DMSO-d₆),δ ppm 0.83 (s, 9 H), 0.90 (s, 9 H), 1.43 (d, J=5.15 Hz, 6 H), 1.53 (m, 2H), 2.36 (m, 1 H), 2.65 (m, 3 H), 2.79 (m, 1 H), 2.99 (m, 1 H), 3.20 (m,3 H), 3.50 (s, 3 H), 3.65 (m, 1 H), 3.85 (d, J=9.93 Hz, 1 H), 4.05 (m, 3H), 4.45 (m, 3 H), 6.63 (d, J=9.93 Hz, 1 H), 7.08 (m, 6 H), 7.22 (d,J=8.09 Hz, 2 H), 7.31 (m, 1 H), 7.46 (d, J=9.56 Hz, 1 H), 7.54 (d,J=7.72 Hz, 1 H), 7.83 (m, 6 H), 8.64 (d, J=4.78 Hz, 1 H).

EXAMPLE 46methyl(1S)-1-[({(1R,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2,4-dioxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 46Atert-butyl(2S)-2-[(2-ethoxy-2-oxoethyl)amino]-3,3-dimethylbutanoate

A solution of L-tert-leucine tert-butyl ester hydrochloride (5 g, 22.34mmol) in DMF (25 mL) was treated with triethylamine (3.1 mL, 22.34 mmol)and the mixture was stirred for 1 hour. The reaction was filtered toremove solid salts, and the filtrate was treated with triethylamine (9.3mL, 67.0 mmol) and ethyl bromoacetate (9.9 mL, 67.0 mmol), and thereaction was stirred for 3 hours at 25° C. The solvent was concentratedand the reaction was partitioned between dichloromethane and water. Theorganic phase was washed with brine and dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with0-20% ethyl acetate/hexane to give the title compound (5.47 g, 90%yield).

EXAMPLE 46Btert-butyl(2S)-2-[(aminocarbonyl)(2-ethoxy-2-oxoethyl)amino]-3,3-dimethylbutanoate

A solution containing the product from Example 46A (5.74 g, 20.0 mmol)in dichloromethane (40 mL) at 0° C. was treated with chlorosulfonylisocyanate (2.26 mL, 26.0 mmol) and the mixture was stirred at 0° C. for2 hours. Water (40 mL) was added to the cold reaction and the mixturewas warmed to 25° C. and stirred for 2 hours. The reaction mixture waspartitioned between dichloromethane and water, and the organic phase waswashed with brine and dried over MgSO₄, filtered and concentrated togive the title compound, which was used without further purification.

EXAMPLE 46Ctert-butyl(2S)-2-(2,4-dioxo-1-imidazolidinyl)-3,3-dimethylbutanoate

A solution containing the product from Example 46B (20.0 mmol) inmethanol (30 mL) was treated with triethylamine (5.6 mL, 40.2 mmol),stirred at 50° C. for 2 hours, and concentrated. The residue waschromatographed on silica gel eluting with 0-30% ethylacetate/dichloromethane to give the title compound (4.57 g, 85% yield).

EXAMPLE 46Dtert-butyl(2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2,4-dioxo-1-imidazolidinyl}butanoate

A solution containing the product from Example 46C (0.112 g, 0.413 mmol)in dichloromethane (3 mL) at 0° C. was treated with6-methyl-2-pyridinemethanol (0.056 g, 0.454 mmol), triphenylphosphine(0.141 g, 0.537 mmol), followed by diethyl azodicarboxylate (0.084 mL,0.537 mmol), stirred at 25° C. for 16 hours, treated with water (3 mL),stirred for 2 hours at 25° C., and partitioned between dichloromethaneand water. The organic phase was washed with brine and dried over MgSO₄,filtered and concentrated. The residue was chromatographed on silica geleluting with 0-30% ethyl acetate/dichloromethane to give the titlecompound (0.151 g, 97% yield).

EXAMPLE 46E(2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2,4-dioxo-1-imidazolidinyl}butanoicacid

A solution containing the product from Example 46D (0.151 g, 0.403 mmol)in dichloromethane (3 mL) was treated with trifluoracetic acid (3 mL),and the mixture was stirred at 25° C. for 16 hours. The solvent wasconcentrated and the product was purified by reversed phasechromatography on a C18 column eluting with a gradient starting with5-100% acetonitrile in water (0.1% TFA) to give the title compound(0.141 g, 81% yield) as the trifluoroacetic acid salt.

EXAMPLE 46Fmethyl(1S)-1-[({(1R,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2,4-dioxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 1H (0.020 g, 0.038 mmol)in THF (0.4 mL) was treated with the product from Example 46E (0.020 g,0.046 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine(0.030 mL, 0.172 mmol), stirred at 25° C. for 2 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was chromatographed on silica geleluting with 0-100% ethyl acetate/dichloromethane to give the titlecompound (0.023 g, 73% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.82 (s,9 H), 0.87 (s, 9 H), 1.32 (m, 1 H), 1.53 (t, J=11.40 Hz, 1 H), 2.41 (s,3 H), 2.63 (m, 3 H), 2.85 (m, 1 H), 3.16 (d, J=18.02 Hz, 1 H), 3.60 (m,5 H), 3.90 (m, 3 H), 4.19 (m, 1 H), 4.35 (s, 1 H), 4.68 (m, 2 H), 6.90(d, J=9.93 Hz, 1 H), 7.03 (m, 6 H), 7.16 (d, J=7.72 Hz, 1 H), 7.25 (d,J=8.09 Hz, 2 H), 7.34 (m, 1 H), 7.69 (t, J=7.72 Hz, 1 H), 7.93 (m, 6 H),8.65 (d, J=4.78 Hz, 1 H).

EXAMPLE 47 1:1 mixture of(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl(1S,2S,4R)-1-benzyl-2-hydroxy-4-({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-5-[4-(2-pyridinyl)phenyl]pentylcarbamateand(3R,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-yl(1S,2S,4R)-1-benzyl-2-hydroxy-4-({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-5-[4-(2-pyridinyl)phenyl]pentylcarbamate

A solution of the product from Example 1H (0.020 g, 0.038 mmol) in THF(0.25 mL) was treated with N,N-diisopropylethylamine (0.015 mL, 0.086mmol) and the product from Example 26A (0.017 g, 0.058 mmol), stirred at25° C. for 1 hour, and partitioned between ethyl acetate and 10% Na₂CO₃solution. The organic phase was washed with additional 10% Na₂CO₃solution and brine, dried over MgSO₄, filtered and concentrated. Theresidue was chromatographed on silica gel eluting with 0-100% ethylacetate/dichloromethane to give the title compound (0.018 g, 70% yield).¹H NMR(300 MHz, DMSO-d₆), δ ppm 0.76 (d, J=3.31 Hz, 9 H), 1.43 (m, 3 H),2.68 (m, 5 H), 3.71 (m, 12 H), 4.18 (m, 1 H), 4.85 (m, 1 H), 5.52 (m, 1H), 6.89 (m, 1 H), 6.99 (m, 1 H), 7.23 (m, 8 H), 7.94 (m, 5 H), 8.65 (d,J=4.78 Hz, 1 H).

EXAMPLE 48methyl(1S)-1-[({(1R,3S,4S)-4-{[(2S)-3,3-dimethyl-2-(2-oxo-3-{[2-(3-pyridinyl)-1,3-thiazol-4-yl]methyl}-1-imidazolidinyl)butanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 1H (0.020 g, 0.038 mmol)in THF (0.4 mL) was treated with the product from Example 19D (0. 022 g,0.045 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine(0.030 mL, 172 mmol), stirred at 25° C. for 2 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was purified by chromatography onsilica gel eluting with 0-100% ethyl acetate/dichloromethane, followedby 0-7.5% methanol in ethyl acetate to give the title compound (0.026 g,78% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.80 (s, 9 H), 0.88 (s, 9H), 1.46 (m, 2 H), 2.44 (d, J=8.82 Hz, 1 H), 263 (m, 3 H), 2.83 (m, 1H), 3.15 (m, 3 H), 3.54 (m, 4 H), 3.84 (d, J=9.56 Hz, 1 H), 3.93 (m, 1H), 4.04 (s, 1 H), 4.18 (m, 1 H), 4.46 (m, 3 H), 6.88 (d, J=9.56 Hz, 1H), 6.96 (m, 1 H), 7.06 (m, 4 H), 7.24 (d, J=8.46 Hz, 2 H), 7.32 (m, 1H), 7.53 (m, 2 H), 7.60 (s, 1 H), 7.89 (m, 5 H), 8.29 (m, 1 H), 8.65 (m,2 H), 9.13 (d, J=1.47 Hz, 1 H).

EXAMPLE 49methyl(1S)-1-[({(1R,3S,4S)-4-{[(2,6-dimethylphenoxy)acetyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 1H (0.020 g, 0.038 mmol)in THF (0.4 mL) was treated with 2,6-dimethylphenoxy acetic acid (U.S.Pat. No. 5,914,332, see Example 1H) (0.008 g, 0.044 mmol), DEPBT (0.017g, 0.057 mmol), and N,N-diisopropylethylamine (0.030 mL, 0.172 mmol),stirred at 25° C. for 2 hours, and partitioned between ethyl acetate and10% Na₂CO₃ solution. The organic phase was washed with additional 10%Na₂CO₃ solution and brine, dried over MgSO₄, filtered and concentrated.The residue was chromatographed on silica gel eluting with 0-100% ethylacetate/dichloromethane to give the title compound (0.019 g, 73% yield).¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.76 (s, 9 H), 1.41 (t, J=11.77 Hz, 1H), 1.58 (m, 1 H), 2.10 (s, 6 H), 2.77 (m, 4 H), 3.57 (s, 3 H), 3.65 (m,1 H), 3.81 (d, J=9.56 Hz, 1 H), 4.07 (m, 4 H), 5.02 (d, J=5.52 Hz, 1 H),6.92 (m, 4 H), 7.25 (m, 8 H), 7.56 (d, J=9.56 Hz, 1 H), 7.85 (m, 3 H),7.96 (d, J=8.46 Hz, 2 H), 8.64 (d, J=4.41 Hz, 1 H).

EXAMPLE 50methyl(1S)-1-[({(1R,3S,4S)-3-hydroxy-4-{[(2S)-2-(3-{[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

Method A

A solution containing the product of Example 1H (0.72 g, 1.35 mmol) inTHF (12 mL) was treated with the product from Example 17F (0.54 g, 1.16mmol), DEPBT (0.52 g, 1.74 mmol), and N,N-diisopropylethylamine (1.0 mL,5.74 mmol), stirred at 25° C. for 16 hours, and partitioned betweenethyl acetate and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with50-100% ethyl acetate in chloroform to give the title compound (0.84 g,84% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.79 (s, 9 H), 0.87 (s, 9H), 1.37 (m, 1 H), 1.41 (s, 3 H), 1.43 (s, 3 H), 1.52 (m, 1 H), 2.48 (m,1H), 2.64 (m, 3 H), 2.83 (dd, J=14.0, 6.6 Hz, 1 H), 3.01 (m, 1 H), 3.15(m, 1 H), 3.23 (m, 1 H), 3.53 (m, 1 H), 3.56 (s, 3H), 3.83 (d, J=9.56Hz, 1 H), 3.93 (m, 1 H), 4.02 (s, 1 H), 4.17 (m, 1 H), 4.39 (m, 3 H),5.15 (s, 1 H), 6.87 (d, J=10.30 Hz, 1 H), 7.08 (m, 6 H), 7.24 (d, J=8.46Hz, 2 H), 7.32 (m, 1 H), 7.52 (m, 2 H), 7.75 (t, J=7.72 Hz, 1 H), 7.89(m, 3 H), 7.95 (d, J=8.46 Hz, 2 H), 8.64 (d, J=4.78 Hz, 1 H).

Method B

EXAMPLE 50-1 methyl 6-(hydroxymethyl)pyridine-2-carboxylate

A suspension of dimethyl 2,6-pyridine-dicarboxylate (100 g, 513 mmol) inmethanol (800 mL) and tetrahydrofuran (300 mL) was heated to dissolveand while the solution was still hot, it was treated in portions withsodium borohydride (18.2 g, 479 mmol) over 1 hour. The mixture wasstirred for 1 hour at room temperature, cooled to 0-5° C., and quenchedwith 10% citric acid (160 mL), stirred for another 15 minutes, andfiltered. The filtrate was concentrated, dissolved in dichloromethane,dried (sodium sulfate), filtered, and concentrated to a white solid. Thesolid was heated to dissolve in ethyl acetate (100 mL), stirred for 16hours at room temperature, filtered and concentrated to give the titlecompound (44.5 g, 56% yield). ¹H NMR (CDCl₃) δ ppm 3.50(s, 1H), 4.00 (s,3 H), 4.86 (s, 2 H), 7.52 (d, 1 H), 7.85 (t, 1 H), 8.04 (d, 1 H).

EXAMPLE 50-2 methyl 6-formylpyridine-2-carboxylate

To a solution of 2M oxalyl chloride/dichloromethane (236 mL, 462 mmol)in dichloromethane (800 mL) at −45° C. was slowly addeddimethylsulfoxide (48.4 mL, 682 mmol) keeping temperature below −45° C.The mixture was stirred for 30 minutes at −45° C. after the addition,and a solution of the product of Example 50-1 (46 g, 276 mmol) indichloromethane (160 mL) was added dropwise, stirred for 30 minutes at−45° C., treated with triethylamine (175 mL, 1256 mmol), stirred for 15minutes at −45° C., removed dry ice bath, stirred at −40 to −50 C for 30minutes, and quenched with pH 7 phosphate buffer solution (250 mL). Theorganic layer was separated and concentrated. This residue was heated todissolve in ethyl acetate (100 mL), cooled to room temperature, stirredat room temperature for 1-2 hours and 1 hour at 0° C. The resultingprecipitate was filtered and washed with cold ethyl acetate (100 mL) togive the title compound (30 g, 69%). ¹H NMR (CDCl₃) δ ppm 4.07 (s, 3 H),8.05 (m, 1 H), 8.16 (m, 1 H), 8.36 (m, 1 H), 10.18 (d, 1 H).

EXAMPLE 50-3 methyl6-{[(2-{[(1R)-1-(tert-butoxycarbonyl)-2,2-dimethylpropyl]amino}ethyl)amino]methyl}pyridine-2-carboxylate

A suspension of the product of Example 50-2 (40 g, 242 mmol), theproduct of Example 111-3 (64 g, 278 mmol), and magnesium sulfate (144 g,1.2 mol) in dichloromethane (600 mL) was stirred at room temperatureovernight, filtered and the filtrate was concentrated. The resultingresidue was dissolved in methanol (600 mL) and treated with sodiumborohydride (10.56 g, 277 mmol) at 0° C. The mixture was stirred for 0.5hour at 0° C., quenched with acetone (10 mL), concentrated, treated withethyl acetate (1 L), and washed with NaHCO₃ (2×200 mL). The organiclayer was dried over MgSO₄, filtered and concentrated to give the crudeproduct (113 g). The residue was chromatographed on silica gel (750 g),eluted with 4 L of 30% ethyl acetate in hexane, 4 L of 50% ethyl acetatein hexane, then 8 L of 10% methanol in dichloromethane to afford thetitle compound (85 gm, 92.5% yield). ¹H NMR (CDCl₃): δ ppm 0.96 (s, 9H), 1.47 (s, 9 H), 2.54 (m, 1 H), 2.76 (m, 4 H), 3.99 (s, 3 H), 4.02 (d,2 H), 7.62 (d, 1 H), 7.80 (t, 1 H), 7.99 (d, 1 H).

EXAMPLE 50-4 methyl6-({3-[(1S)-1-(tert-butoxycarbonyl)-2,2-dimethylpropyl]-2-oxoimidazolidin-1-yl}methyl)pyridine-2-carboxylate

A solution of the product of Example 50-3 (92 g, 243 mmol),disuccinimidyl carbonate (78 g, 304 mmol), and triethylamine (41 mL, 294mmol) in 1,2-dichloroethane (1.8 L) was stirred at room temperature for16 hours. The mixture was diluted with dichloroethane (200 mL), washedwith saturated NaHCO₃ (2×500 mL), and brine (200 mL), dried over MgSO₄,filtered and concentrated. The residue was triturated with hexane (550mL) and ethyl acetate (50 mL) at room temperature for two hours to givethe title compound as a white solid (85 gm, 98% yield). ¹H NMR (CDCl₃):δ ppm 1.10 (s, 9 H), 1.48 (s, 9 H), 3.34 (m, 2 H), 3.62 (m, 1 H), 3.88(m, 1 H), 4.00 (s, 3 H), 4.42 (s, 1 H), 4.64 (s, 2 H), 7.52 (d, 1 H),7.81 (t, 1 H), 8.03 (d, 1 H).

EXAMPLE 50-5tert-butyl(2S)-2-(3-{[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]methyl}-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoate

A solution of the product of Example 50-4 (46 g, 114 mmol) intetrahydrofuran(1 L) at 0° C. was treated with methylmagnesium bromidein diethyl ether (3M, 190 mL, 570 mmol), stirred for 1 hour at 0° C.,quenched with 10% citric acid (160 mL), and extracted with ethyl acetate(200 mL). The aqueous layer was washed with ethyl acetate (200 mL). Thecombined organic layer was washed with brine (200 mL), dried over MgSO₄,filtered and concentrated to 54.7 g of crude material. The crudematerial was filtered through silica pad, washed with ethyl acetate (1.2L), and concentrated. The residue was crystallized from hexane (400 mL)to give the title compound as solid (30 gm, 69%). ¹H NMR (CDCl₃): δ ppm1.09 (s, 9 H), 1.47 (s, 9 H), 1.47 (s, 9 H), 1.52 (s, 6 H), 3.34 (m, 2H), 3.62 (m, 1 H), 3.89 (m, 1 H), 4.41 (s, 1 H), 4.53 (m, 2 H), 5.20 (s,1 H), 7.21 (m, 2 H), 7.67 (t, 1 H).

EXAMPLE 50-6(2S)-2-(3-{[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]methyl}-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoicacid

The product of Example 50-5 (61 g, 150.6 mmol) at 25° C. was treatedwith 90% trifluoroacetic acid in water (300 mL). The reaction wasstirred at 25° C. for 5 hours and concentrated to give 118 g of residue.The residue was loaded on 600 g of silica gel, eluted with 4 L of 5%methanol in dichloromethane, then with 4 L of 10% methanol indichloromethane. The desired fractions were combined and concentrated togive 100 g of crude material. The crude material was crystallized fromdiethyl ether (350 mL) to afford 54 g of the trifluoroacetic acid saltof the title compound, 77% yield. ¹H NMR (CDCl₃): δ ppm 1.10 (s, 9 H,)1.63 (s, 6 H), 3.48 (m, 2 H), 3.65 (m, 1 H), 3.87 (m, 1H), 4.33 (s, 1H), 4.78 (q, 2 H), 7.54 (d, 1 H), 7.61 (d, 1 H), 8.12 (t, 1 H), 9.2(w,3H).

EXAMPLE 50-7N¹-[(1R,3S,4S)-4-amino-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]-N²-(methoxymethyl)-3-methyl-L-valinamide

The product of Example 111-13A (21.746 g; 27:1 diastereomeric ratio) inisopropyl acetate (217 mL) was treated with concentrated hydrochloricacid (43.5 of mL), stirred at room temperature for 5 minutes, anddiluted with water (168 mL). The aqueous layer was diluted withchloroform (440 mL) and the pH was adjusted to about 10 with K₂CO₃ (52.5g). The chloroform layer was concentrated to oil, chased with ethanol(220 mL) to a solid. The solid was crystallized from 105 mL ofethanol/105 mL of water to give 16.57 g of the title compound. ¹H NMR(CDCl₃) δ ppm 0.89 (s, 9 H,) 1.55 (m, 1H), 1.75 (m, 1 H), 2.36 (m, 1 H),2.78 (m, 2 H), 2.88 (m, 1H), 3.02 (m, 1H), 3.50 (m, 1H), 3.65 (s, 3H),3.85 (d, 1H), 4.54 (m, 1 H), 5.45 (d, 1 H), 6.63, (d, 1H), 7.18 (m, 4H),7.28 (m, 4 H), 7.70 (m, 2 H), 7.90(d, 2H), 8.66 (d, 1H).

EXAMPLE 50-8methyl(1S)-1-[({(1R,3S,4S)-3-hydroxy-4-{[(2S)-2-(3-{[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A mixture of the product of Example 50-6 ( 16.27 g, 35 mmol, 1.1equivalents), DEPBT (13.37 g, 45 mmol, 1.4 equivalents), tetrahydrofuran(170 mL), and K₂CO₃(8.82 g, 64 mmol, 2 equivalents) was stirred for 2.5hours at 20° C., treated with a solution of the product of Example 50-7(17 g, 32 mmol, 1 equivalent) in tetrahydrofuran (170 mL), stirred at20° C. for 15 hours, treated with 10% Na₂CO₃ (340 mL), stirred at 20° C.for 6 hours, and extracted with ethyl acetate (340 mL). The organicphase was washed with 10% brine (340 mL) and 20% brine (340 mL), andconcentrated. The residue was chromatographed on silica gel (260 gmsilica gel, eluted with dichloromethane, 2.5% of methanol indichloromethane, 5% methanol in dichloromethane, 7.5% methanol indichloromethane, and 10% methanol in dichloromethane). The desiredfractions were pooled, concentrated to foam, chased with ethyl acetate(250 mL) to oil, then twice with dichloromethane. 28.4 gm of solid wasremoved from the flask. The remaining solid was dissolved in heptanes(100 mL) at 100° C., cooled to 75° C., after 30 minutes added 100 mL ofethyl acetate and 100 mL of heptanes, held at 80° C. for 15 minutes,cooled to room temperature, filtered to give crystalline seeds. 28.4 gmof amorphous solid was slurried in 150 mL of heptanes and 25 mL of ethylacetate at 100° C., cooled to 75° C., added seeds from the small lot,added 50 mL of ethyl acetate, heated to 85° C., cooled to roomtemperature, filtered and washed with 2×50 mL of heptanes, dried to give26.6 gm of the title compound. ¹H NMR(DMSO-d₆) δ ppm 0.79 (s, 9 H,) 0.88(s, 9 H), 1.37 (m, 1H), 1.40 (s, 3H), 1.42 (s, 3H), 1.53 (m, 1H), 2.45(m, 1H), 2.63 (m, 3H), 2.82 (m, 1H), 2.99 (m, 1H), 3.17 (m, 2H), 3.53(m, 1 H), 3.57 (s, 3H), 3.82 (d, 1 H), 3.93 (m, 1 H), 4.01 (s, 1 H),4.17 (m, 1H), 4.38 (m, 3H), 5.17 (s, 1 H), 6.85 (d, 1H), 7.05 (m, 6H),7.22 (d, 2 H), 7.30 (t, 1 H), 7.51 (m, 2H), 7.73 (t, 1H), 7.85 (m, 3H),7.94 (d, 2H), 8.62(d, 1H).

EXAMPLE 51methyl(1S)-1-[({(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2,4-dioxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 2C (0.020 g, 0.038 mmol)in THF (0.4 mL) was treated with the product from Example 46E (0.020 g,0.046 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine(0.035 mL, 0.201 mmol), stirred at 25° C. for 1 hour, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was chromatographed on silica geleluting with 0-100% ethyl acetate/dichloromethane to give the titlecompound (0.020 g, 64% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.85 (s,9 H), 0.88 (s, 9 H), 1.54 (m, 2 H), 2.41 (s, 3 H), 2.65 (m, 4 H), 3.08(d, J=18.02 Hz, 1 H), 3.51 (s, 3 H), 3.72 (m, 1 H), 3.89 (m, 2 H), 4.17(m, 2 H), 4.39 (s, 1 H), 4.67 (m, 3 H), 6.66 (d, J=9.93 Hz, 1 H), 7.06(m, 7 H), 7.23 (d, J=8.46 Hz, 2 H), 7.31 (m, 1 H), 7.66 (t, J=7.54 Hz, 1H), 7.87 (m, 6 H), 8.64 (d, J=4.41 Hz, 1 H).

EXAMPLE 52methyl(1S)-1-[({(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2,4-dioxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 23S (0.020 g, 0.038 mmol)in THF (0.4 mL) was treated with the product from Example 46E (0.020 g,0.046 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine(0.035 mL, 0.201 mmol), stirred at 25° C. for 1 hour, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was chromatographed on silica geleluting with 0-100% ethyl acetate/dichloromethane to give the titlecompound (0.021 g, 67% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.80 (s,9 H), 0.88 (s, 9 H), 1.55 (m, 2 H), 2.29 (m, 1 H), 2.39 (s, 3H), 2.75(m, 3 H), 3.15 (d, J=18.38 Hz, 1 H), 3.52 (s, 3 H), 3.61 (m, 1 H), 3.94(m, 2 H), 4.19 (m, 3 H), 4.68 (d, J=10.30 Hz, 2 H), 4.89 (d, J=5.52 Hz,1 H), 6.83 (d, J=9.93 Hz, 1 H), 7.00 (m, 6 H), 7.13 (d, J=7.72 Hz, 1 H),7.31 (m, 3 H), 7.64 (m, 2 H), 7.88 (m, 4 H), 8.09 (d, J=9.19 Hz, 1 H),8.63 (d, J=4.78 Hz, 1 H).

EXAMPLE 53methyl(1S)-1-[({(1R,3S,4)-4-({(2S)-3,3-dimethyl-2-[2-oxo-3-(4-quinolinylmethyl)-1-imidazolidinyl]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 1H (0.020 g, 0.038 mmol)in THF (0.4 mL) was treated with the product from Example 42B (0.020 g,0.045 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine(0.035 mL, 0.201 mmol), stirred at 25° C. for 2 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was chromatographed on silica geleluting with 0-100% ethyl acetate/dichloromethane, followed by 0-0.5%methanol in ethyl acetate, to give the title compound (0.021 g, 65%yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.81 (s, 9 H), 0.89 (s, 9 H),1.26 (m, 1 H), 1.37 (m, 1 H), 1.53 (m, 1 H), 2.30 (m, 1 H), 2.65 (m, 2H), 2.85 (m, 2 H), 3.00 (m, 1 H), 3.18 (m, 1 H), 3.53 (m, 4 H), 3.84 (d,J=9.56 Hz, 1 H), 3.94 (m, 1 H), 4.05 (m, 1 H), 4.19 (m, 1 H), 4.44 (d,J=7.35 Hz, 1 H), 4.63 (d, J=15.44 Hz, 1 H), 4.95 (d, J=15.44 Hz, 1 H),6.87 (m, 6 H), 7.25 (d, J=8.46 Hz, 2 H), 7.32 (m, 1 H), 7.43 (d, J=4.41Hz, 1 H), 7.60 (m, 2 H), 7.86 (m, 6 H), 8.06 (d, J=7.72 Hz, 1 H), 8.30(d, J=8.09 Hz, 1 H), 8.65 (m, 1 H), 8.90 (d, J=4.04 Hz, 1 H).

EXAMPLE 54methyl(1S)-1-[({(1S,3S,4S)-4-({(2S)-3,3-dimethyl-2-[(phenoxyacetyl)amino]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 54Atert-butyl(2S)-3,3-dimethyl-2-[(phenoxyacetyl)amino]butanoate

A solution of L-tert-Leucine tert-butyl ester hydrochloride (0.20 g,0.90 mmol) in THF (9 mL) at 0° C. was treated with triethylamine (0.38mL, 2.73 mmol) and phenoxyacetyl chloride (0.14 mL, 1.01 mmol), stirredat 0° C. for 15 minutes and then at 25° C. for 2 hours. The reactionmixture was partitioned between ethyl acetate and water. The organicphase was washed with brine and dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with0-10% ethyl acetate/chloroform to give the title compound (0.23 g, 80%yield).

EXAMPLE 54B (2S)-3,3-dimethyl-2-[(phenoxyacetyl)amino]butanoic acid

A solution of the product from Example 54A (0.012 g, 0.038 mmol) indichloromethane (0.2 mL) was treated with trifluoroacetic acid (0.2 mL)and the reaction was stirred at 25° C. for 1 hour and concentrated. Theconcentrate was azeotroped with toluene to give the title compound,which was used without further purification.

EXAMPLE 54Cmethyl(1S)-1-[({(1S,3S,4S)-4-({(2S)-3,3-dimethyl-2-[(phenoxyacetyl)amino]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 2C (0.020 g, 0.038 mmol)in THF (0.4 mL) was treated with the product from Example 54B (0.038mmol), DEPBT (0.016 g, 0.054 mmol), and N,N-diisopropylethylamine (0.032mL, 0.184 mmol), stirred at 25° C. for 2 hours, and partitioned betweenethyl acetate and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was purified by reversed phase chromatographyon a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA) togive the title compound (0.011 g, 38% yield). ¹H NMR (300 MHz, DMSO-d₆),δ ppm 0.80 (d, J=2.94 Hz, 18 H), 1.53 (m, 2 H), 2.55 (m, 1 H), 2.73 (m,3 H), 3.49 (s, 3 H), 3.65 (m, 1 H), 3.82 (d, J=9.93 Hz, 1 H), 4.05 (m, 1H), 4.15 (m, 1 H), 4.33 (d, J=9.56 Hz, 1 H), 4.53 (m, 2 H), 4.81 (d,J=5.88 Hz, 1 H), 6.61 (d, J=9.56 Hz, 1 H), 6.95 (m, 3 H), 7.11 (m, 1 H),7.18 (m, 6 H), 7.31 (m, 3 H), 7.48 (d, 9.56 Hz, 1 H), 7.84 (m, 6 H),8.64 (d, J=4.41 Hz, 1 H).

EXAMPLE 55methyl(1S,4S,6S,7S,10S)-7-benzyl-1,10-ditert-butyl-6-hydroxy-2,9,12-trioxo-4-[4-(2-pyridinyl)benzyl]-14-oxa-3,8,11-triazapentadec-1-ylcarbamateEXAMPLE 55Atert-butyl(2S)-2-[(methoxyacetyl)amino]-3,3-dimethylbutanoate

A solution of L-tert-Leucine tert-butyl ester hydrochloride (0.20 g,0.90 mmol) in THF (9 mL) at 0° C. was treated with triethylamine (0.38mL, 2.73 mmol) and methoxyacetyl chloride (0.09 mL, 0.98 mmol), stirredat 0° C. for 15 minutes and then at 25° C. for 2 hours. The reaction waspartitioned between ethyl acetate and water. The organic phase waswashed with brine and dried over MgSO₄, filtered and concentrated. Theresidue was chromatographed on silica gel eluting with 0-33% ethylacetate/chloroform to give the title compound (0.266 g).

EXAMPLE 55B (2S)-2-[(methoxyacetyl)amino]-3,3-dimethylbutanoic acid

A solution of the product from Example 55A (0.012 g, 0.038 mmol) indichloromethane (0.2 mL) was treated with trifluoroacetic acid (0.2 mL),stirred at 25° C. for 1 hour and concentrated. The residue wasazeotroped with toluene to give the title compound, which was usedwithout further purification.

EXAMPLE 55Cmethyl(1S,4S,6S,7S,10S)-7-benzyl-1,10-ditert-butyl-6-hydroxy-2,9,12-trioxo-4-[4-(2-pyridinyl)benzyl]-14-oxa-3,8,11-triazapentadec-1-ylcarbamate

A solution containing the product from Example 2C (0.020 g, 0.038 mmol)in THF (0.4 mL) was treated with the product from Example 55B (0.038mmol), DEPBT (0.016 g, 0.054 mmol), and N,N-diisopropylethylamine (0.032mL, 0.184 mmol), stirred at 25° C. for 2 hours, and partitioned betweenethyl acetate and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was purified by reversed phase chromatographyon a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA) togive the title compound (0.011 g, 38% yield). ¹H NMR (300 MHz, DMSO-d₆),δ ppm 0.81 (s, 9 H), 0.84 (s, 9 H), 1.52 (m, 2 H), 2.56 (m, 1 H), 2.74(m, 3 H), 3.26 (s, 3 H), 3.49 (s, 3 H), 3.66 (m, 1 H), 3.82 (m, 3 H),4.03 (m, 1 H), 4.16 (m, 1 H), 4.31 (d, J=9.56 Hz, 1 H), 4.83 (d, J=5.88Hz, 1 H), 6.62 (d, J=9.56 Hz, 1 H), 7.14 (m, 8 H), 7.31 (m, 1 H), 7.85(m, 6 H), 8.63 (d, J=4.41 Hz, 1 H).

EXAMPLE 56methyl(1S)-1-[({(1S,3S,4S)-3-hydroxy-4-[((2S)-2-{3-[(2-isopropyl-1,3-thiazol-4-yl)methyl]-2,4-dioxo-1-imidazolidinyl}-3-methylpentanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 56A 2-methylpropanethioamide

A solution containing isobutyramide (10 g, 115 mmol) in THF (250 mL) wastreated with phosphorous pentasulfide (4.1 g, 9.22 mmol), stirred at 25°C. for 64 hours, concentrated and partitioned between ethyl acetate andwater. The organic phase was washed with brine and dried over MgSO₄,filtered and concentrated to give the title compound (8.6 g, 73% yield),which was used without further purification.

EXAMPLE 56B ethyl 2-isopropyl-1,3-thiazole-4-carboxylate

A solution containing the product from Example 56A (8.6 g, 83.5 mmol) inethanol (250 mL) was treated with ethyl bromopyruvate (12.6 mL, 100mmol), and the mixture was heated at 70° C. for 3 hours, cooled to 25°C., concentrated, and partitioned between dichloromethane and saturatedNaHCO₃. The organic phase was washed with brine and dried over MgSO₄,filtered and concentrated to give the title compound (18 g, 57% yield),which was used without further purification.

EXAMPLE 56C (2-isopropyl-1,3-thiazol-4-yl)methanol

A solution containing the product from Example 56B (18 g, 90.5mmol) indichloromethane (100 mL) was treated with diisobutyl aluminum hydride(150 mL, 1 M in dichloromethane) dropwise at −78° C. over 2 hours andthe mixture was stirred at −78° C. for 2 hours. Acetic acid (10 mL) wasadded at −78° C. and the mixture was warmed to 25° C. A 10% solution ofaqueous sodium potassium tartrate was added and the mixture was stirredvigorously for 1 hour. The reaction was partitioned betweendichloromethane and water, and the organic phase was washed with brineand dried over MgSO₄, filtered and concentrated. The residue waschromatographed on silica gel eluting with 0-5% ethylacetate/dichloromethane to give the title compound (3.84 g, 27% yield).

EXAMPLE 56Dtert-butyl(2S,3S)-2-{3-[(2-isopropyl-1,3-thiazol-4-yl)methyl]-2,4-dioxo-1-imidazolinyl}-3-methylpentanoate

A solution containing the product from Example 36C (0.076 g, 0.281 mmol)in dichloromethane (2 mL) at 0° C. was treated with the product fromExample 56C (0.049 g, 0.309 mmol), triphenylphosphine (0.096 g, 0.365mmol), followed by diethyl azodicarboxylate (0.057 mL, 0.365 mmol),stirred at 25° C. for 16 hours. Water (3 mL) was added and the reactionwas stirred for 2 hours at 25° C. The reaction mixture was partitionedbetween dichloromethane and water, and the organic phase was washed withbrine and dried over MgSO₄, filtered and concentrated. The residue waspurified by reversed phase chromatography on a C18 column eluting with5-100% acetonitrile in water (0.1% TFA) to give the title compound(0.090 g, 78% yield).

EXAMPLE 56E(2S,3S)-2-{3-[(2-isopropyl-1,3-thiazol-4-yl)methyl]-2,4-dioxo-1-imidazolidinyl}-3-methylpentanoicacid

A solution containing the product from Example 56D (0.090 g, 0.220 mmol)in dichloromethane (2 mL) was treated with trifluoracetic acid (2 mL),stirred at 25° C. for 16 hours, and concentrated. The residue waspurified by reversed phase chromatography on a C18 column eluting with5-100% acetonitrile in water (0.1% TFA) to give the title compound (0.1g) as the trifluoroacetic acid salt.

EXAMPLE 56Fmethyl(1S)-1-[({(1S,3S,4S)-3-hydroxy-4-[((2S)-2-{3-[(2-isopropyl-1,3-thiazol-4-yl)methyl]-2,4-dioxo-1-imidazolidinyl}-3-methylpentanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 2C (0.030 g, 0.056 mmol)in THF (0.5 mL) was treated with the product from Example 56E (0.026 g,0.073 mmol), DEPBT (0.025 g, 0.085 mmol), and N,N-diisopropylethylamine(0.049 mL, 0.282 mmol), stirred at 25° C. for 1 hour, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was chromatographed on silica geleluting with 0-100% ethyl acetate/dichloromethane, followed by elutionwith 0-5% methanol in ethyl acetate to give the title compound (0.033 g,67% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.66 (d, J=6.62 Hz, 3 H),0.73 (t, J=7.35 Hz, 3 H), 0.88 (m, 12 H), 1.26 (s, 3 H), 1.29 (s, 3 H),1.50 (m, 2 H), 1.73 (m, 1 H), 2.69 (m, 4 H), 3.10 (d, J=18.38 Hz, 1 H),3.50 (s, 3 H), 3.78 (m, 3 H) 4.17 (m, 3 H), 4.66 (m, 3 H), 6.67 (d,J=9.93 Hz, 1 H), 6.99 (m, 3 H), 7.07 (m, 2 H), 7.23 (m, 3 H), 7.31 (m, 1H), 7.85 (m, 6 H), 8.63 (d, J=4.41 Hz, 1 H).

EXAMPLE 57methyl(1S)-1-[({(1S,3S,4S)-4-{[(2S)-2-(2,4-dioxo-3-{[2-(3-pyridinyl)-1,3-thiazol-4-yl]methyl}-1-imidazolidinyl)-3-methylpentanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 57A [2-(3-pyridinyl)-1,3-thiazol-4-yl]methanol

A solution containing the product from Example 19 B (0.20 g, 1.05 mmol)in a mixture of THF (1.5 mL) and methanol (1.5 mL) was treated withNaBH₄ (0.052 g, 1.37 mmol), stirred at 25° C. for 2 hours, quenched withsaturated ammonium chloride solution and concentrated. The concentratewas partitioned between ethyl acetate and saturated NaHCO₃. The organicphase was washed with brine and dried over MgSO₄, filtered andconcentrated to give the title compound (0.063 g, 31% yield).

EXAMPLE 57Btert-butyl(2S,3S)-2-(2,4-dioxo-3-{[2-(3-pyridinyl)-1,3-thiazol-4-yl]methyl}-1-imidazolidinyl)-3-methylpentanoate

A solution containing the product from Example 36C (0.081 g, 0.30 mmol)in dichloromethane (2 mL) at 0° C. was treated with the product fromExample 57A (0.063 g, 0.33 mmol), triphenylphosphine (0.103 g, 0.39mmol), followed by diethyl azodicarboxylate (0.061 mL, 0.39 mmol),stirred at 25° C. for 16 hours. Water (3 mL) was added and the reactionwas stirred for 2 hours at 25° C. The reaction mixture was partitionedbetween dichloromethane and water, and the organic phase was washed withbrine and dried over MgSO₄, filtered and concentrated, to give the crudeproduct, which was used without further purification.

EXAMPLE 57C(2S,3S)-2-(2,4dioxo-3-{[2-(3-pyridinyl)-1,3-thiazol-4-yl]methyl}-1-imidazolidinyl)-3-methylpentanoicacid

A solution containing the product from Example 57B (0.090 g, 0.220 mmol)in dichloromethane (2 mL) was treated with trifluoracetic acid (2 mL),stirred at 25° C. for 16 hours, and concentrated. The residue waspurified by reversed phase chromatography on a C18 column eluting with5-100% acetonitrile in water (0.1% TFA) to give the title compound(0.131 g, 90% yield) as the trifluoroacetic acid salt.

EXAMPLE 57Dmethyl(1S)-1-[({(1S,3S,4S)-4-{[(2S)-2-(2,4-dioxo-3-{[2-(3-pyridinyl)-1,3-thiazol-4-yl]methyl}-1-imidazolidinyl)-3-methylpentanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 2C (0.030 g, 0.056 mmol)in THF (0.5 mL) was treated with the product from Example 57C (0.036 g,0.073 mmol), DEPBT (0.025 g, 0.085 mmol), and N,N-diisopropylethylamine(0.049 mL, 0.282 mmol), stirred at 25° C. for 1 hour, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was chromatographed on silica geleluting with 0-100% ethyl acetate/dichloromethane, followed by elutionwith 0-5% methanol in ethyl acetate to give the title compound (0.044g,86% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.67 (d, J=6.62 Hz, 3 H),0.73 (t, J=7.35 Hz, 3 H), 0.90 (m, 12 H), 1.25 (m, 1 H), 1.52 (m, 2 H),1.75 (m, 1 H), 2.69 (m, 3 H), 3.15 (m, 1 H), 3.50 (s, 3 H), 3.78 (m, 2H), 4.16 (m, 3 H), 4.67 (d, J=6.62 Hz, 1 H), 4.78 (m, 2 H), 6.67 (d,J=9.93 Hz, 1 H), 6.96 (m, 3 H), 7.07 (m, 2 H), 7.22 (d, J=8.09 Hz, 2 H),7.31 (m, 1 H), 7.51 (dd, J=7.91, 4.96 Hz, 1 H), 7.64 (s, 1 H), 7.86 (m,6 H), 8.24 (m, 1 H), 8.64 (m, 2 H), 9.08 (d, J=1.84 Hz, 1 H).

EXAMPLE 58methyl(1S)-1-[({(1S,3S,4S)-4-{[(2S)-3,3-dimethyl-2-({[(6-methyl-3-pyridinyl)oxy]acetyl}amino)butanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 58A [(6-methyl-3-pyridinyl)oxy]acetic acid

A solution containing ethyl 6-methyl-3-pyridyloxyacetate (0.026 g, 0.13mmol) in a mixture of THF (0.5 mL) and water (0.5 mL) was treated withlithium hydroxide monohydrate (0.008 g, 0.19 mmol), stirred at 25° C.for 18 hours, aid concentrated to give the crude product, which was usedwithout purification.

EXAMPLE 58Bmethyl(1S,4S,6S,7S,10S)-7-benzyl-1,10-ditert-butyl-6-hydroxy-14,14-dimethyl-2,9,12-trioxo-4-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazapentadec-1-ylcarbamate

A solution containing the product from Example 2C (0.050 g, 0.094 mmol)in THF (0.5 mL) was treated with Boc-L-tert-leucine (0.022 g, 0.096mmol), DEPBT (0.042 g, 0.140 mmol), and N,N-diisopropylethylamine (0.08mL, 0.459 mmol), stirred at 25° C. for 2 hours, and partitioned betweenethyl acetate and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting witha gradient starting with 50-100% ethyl acetate/chloroform to give thetitle compound (0.058 g, 83% yield).

EXAMPLE 58Cmethyl(1S)-1-[({(1S,3S,4S)-4-{[(2S)-2-amino-3,3-dimethylbutanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 58B (0.058 g, 0.078 mmol)in dichloromethane (0.5 mL) was treated with trifluoroacetic acid (0.5mL), stirred at 25° C. for 1 hour, and concentrated. The residue wasazeotroped with toluene to give the title compound as thetrifluoroacetic acid salt, which was used without further purification.

EXAMPLE 58Dmethyl(1S)-1-[({(1S,3S,4S)-4-{[(2S)-3,3-dimethyl-2-({[(6-methyl-3-pyridinyl)oxy]acetyl}amino)butanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 58C (0.03 g, 0.04 mmol)in THF (0.5 mL) was treated with the product from Example 58A (0.13mmol), DEPBT (0.017 g, 0.12 mmol), and N,N-diisopropylethylamine (0.033mL, 0.39 mmol), stirred at 25° C. for 18 hours, and partitioned betweenethyl acetate and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was purified by reversed phase chromatographyon a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA) togive the title compound (0.016 g, 52% yield). ¹H NMR (300 MHz, DMSO-d₆),δ ppm 0.80 (s, 9 H), 0.83 (s, 9 H), 1.25 (m, 1 H), 1.52 (m, 2 H), 2.38(s, 3 H), 2.71 (m, 3 H), 3.49 (s, 3 H), 3.65 (m, 1 H), 3.82 (d, J=9.93Hz, 1 H), 4.10 (m, 2 H), 4.32 (d, J=9.56 Hz, 1 H), 4.58 (m, 2 H), 4.81(d, J=5.88 Hz, 1 H), 6.61 (d, J=9.56 Hz, 1 H), 7.17 (m, 9 H), 7.31 (m, 1H), 7.61 (d, J=9.56 Hz, 1 H), 7.83 (m, 6 H), 8.14 (d, J=2.94 Hz, 1 H),8.63 (d, J=4.41 Hz, 1 H).

EXAMPLE 59methyl(1S)-1-[({(1R,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(1-methyl-1H-benzimidazol-2-yl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 59A2,2-dimethoxy-N-[(1-methyl-1H-benzimidazol-2-yl)methyl]ethanamine

A solution of 1-methyl-2-formylbenzimidazole (1 g) in methanol (27 mL)and acetic acid (0.54 mL) was treated with aminoacetaldehydediethylacetal (0.9 g, 1 eq.) and NaCNBH₃ (0.85 g, 2 eq.) at 25° C.,stirred for 1 hour. The mixture was partitioned between water and ethylacetate. The organic phase layer was separated, washed sequentially withsaturated NaHCO₃ and brine, and concentrated. The residue waschromatographed on silica gel, eluting with 8% methanol/dichloromethaneto give the title compound (1.2 g 64% yield).

EXAMPLE 59B 9H-fluoren-9-ylmethyl2,2-dimethoxyethyl[(1-methyl-1H-benzimidazol-2-yl)methyl]carbamate

A solution of the product of Example 59A (1.2 g) in dichloromethane (30mL) was treated with 9-fluorenylmethyl succinimide (1.6 g, 1.05 eq.) at0° C. for 16 hours. The mixture was partitioned between water and ethylacetate. The organic phase layer was separated, washed sequentially with10% NaHCO₃ and brine, dried over Na₂SO₄, filtered and concentrated. Theresidue was chromatographed on silica gel, eluting with ethyl acetate:dichloromethane (1:1) to give 1.83 g (84% yield) of the title compound.

EXAMPLE 59C9H-fluoren-9-ylmethyl(1-methyl-1H-benzimidazol-2-yl)methyl(2-oxoethyl)carbamate

A solution of the product of Example 59B (0.2 g) in tetrahydrofuran (0.2mL) was treated with 30% HCl (0.2 mL), stirred at 75° C. for 6 hours,cooled to 25° C. and concentrated. The residue was partitioned between10% NaHCO₃ and ethyl acetate, the organic phase layer was separated andwashed with brine, dried over Na₂SO₄, filtered and concentrated to givethe title compound (175 mg).

EXAMPLE 59Dtert-butyl(2S)-2-[(2-{[(9H-fluoren-9-ylmethoxy)carbonyl][(1-methyl-1H-benzimidazol-2-yl)methyl]amino}ethyl)amino]-3,3-dimethylbutanoate

A solution of the product of Example 59C (0.178 g) and (1)-methylt-leucinate hydrochloride (76.1 mg, 1 eq.) in methanol (1.7 mL) andacetic acid (17 μL) was treated with NaCNBH₃ (54 mg, 2 eq.) at 25° C.for 3.5 hours. The mixture was partitioned between water and ethylacetate. The organic phase layer was separated and washed with IN NaHCO₃and brine, and concentrated. The residue was chromatographed on silicagel, eluting with ethyl acetate:dichloromethane (3:1) to give 0.19 g(83% yield) of the title compound.

EXAMPLE 59Etert-butyl(2S)-3,3-dimethyl-2-{3-[(1-methyl-1H-benzimidazol-2-yl)methyl]-2-oxo-1-imidazolidinyl}butanoate

A solution of the product of Example 59D (0.19 g) inN,N-dimethylformamide (3.5 mL) was treated with diethylamine (0.35 mL),stirred at 25° C. for 1.5 hours and concentrated. A solution of theresidue in 1,2-dichloroethane (7 mL) was treated withbis-(p-nitrophenyl) carbonate (0.128 g, 1.2 eq.), stirred at 60° C. for16 hours and concentrated. The residue was chromatographed on silicagel, eluting with ethyl acetate:dichloromethane (3:2) to give 80 mg (64%yield) of the title compound.

EXAMPLE 59F(2S)-3,3-dimethyl-2-{3-[(1-methyl-1H-benzimidazol-2-yl)methyl]-2-oxo-1-imidazolidinyl}butanoicacid

A solution containing the product from Example 59E (0.025 g, 0.070 mmol)in a mixture of THF (0.3 mL) and water (0.3 mL) was treated with lithiumhydroxide monohydrate (0.004 g, 0.094 mmol), and the mixture was stirredat 25° C. for 18 hours. The solvent was concentrated to give the crudeproduct, which was used without purification.

EXAMPLE 59Gmethyl(1S)-1-[({(1R,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(1-methyl-1H-benzimidazol-2-yl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 1H (0.025 g, 0.047 mmol)in THF (0.5 mL) was treated with the product from Example 59F(0.070mmol), DEPBT (0.021 g, 0.070 mmol), and N,N-diisopropylethylamine (0.041mL, 0.240 mmol) and the mixture was stirred at 25° C. for 2 hours. Themixture was partitioned between ethyl acetate and 10% Na₂CO₃ solution.The organic phase was washed with additional 10% Na₂CO₃ solution andbrine, dried over MgSO₄, filtered and concentrated. The product waspurified by reversed phase chromatography on a C18 column eluting with5-100% acetonitrile in water (0.1% TFA). The reaction was partitionedbetween ethyl acetate and saturated NaHCO₃, and the organic phase waswashed with brine and dried over MgSO₄, filtered and concentrated, togive the title compound (0.021 g, 50% yield). ¹H NMR (300 MHz, DMSO-d₆),δ ppm 0.81 (s, 9 H), 0.88 (s, 9 H), 1.38 (m, 1 H), 1.53 (m, 1 H), 2.40(m, 1 H), 2.64 (m, 3 H), 2.83 (m, 1 H), 3.12 (m, 4 H), 3.54 (m, 4 H),3.82 (m, 3 H), 3.95 (m, 1 H), 4.03 (s, 1 H), 4.18 (m, 1 H), 4.43 (d,J=6.99 Hz, 1 H), 4.60 (m, 2 H), 6.92 (m, 4 H), 7.04 (m, 2 H), 7.21 (m, 4H), 7.32 (m, 1 H), 7.58 (m, 3 H), 7.89 (m, 5 H), 8.65 (d, J=4.41 Hz, 1H).

EXAMPLE 60methyl(1S)-1-[({(1R,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(2-methyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 1H (0.030 g, 0.056 mmol)in THF (0.5 mL) was treated with the product from Example 14B (0.023 g,0.073 mmol), DEPBT (0.025 g, 0.085 mmol), and N,N-diisopropylethylamine(0.049 mL, 0.282 mmol) and the mixture was stirred at 25° C. for 16hours. The mixture was partitioned between ethyl acetate and 10% Na₂CO₃solution. The organic phase was washed with additional 10% Na₂CO₃solution and brine, dried over MgSO₄, filtered and concentrated. Theresidue was chromatographed on silica gel eluting with 0-100% ethylacetate/dichloromethane, followed by elution with 0-5% methanol in ethylacetate to give the title compound (0.044 g, 94% yield). ¹H NMR (300MHz, DMSO-d₆), δ ppm 0.80 (s, 9 H), 0.89 (m, 9 H), 1.38 (m, 1 H), 1.53(m, 1 H), 2.43 (m, 1 H),2.63 (m, 6 H), 2.83 (m, 1 H), 3.03 (m, 2 H),3.20 (m, 1 H), 3.53 (m, 4 H), 3.94 (m, 3 H), 4.36 (m, 4 H), 6.88 (d,J=9.56 Hz, 1 H), 7.05 (m, 5 H), 7.24 (m, 3 H), 7.32 (m, 1 H), 7.51 (d,J=9.56 Hz, 1 H), 7.89 (m, 5 H), 8.65 (d, J=4.78 Hz, 1 H).

EXAMPLE 613-pyridinylmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamateEXAMPLE 61Atert-butyl(2S)-3,3-dimethyl-2-{[(3-pyridinylmethoxy)carbonyl]amino}butanoate

A solution containing L-tert-leucine tert-butyl ester hydrochloride(0.20 g, 0.90 mmol) in THF (9 mL) was treated with[(3-pyridinyl)methyl}(4-nitrophenyl)carbonate (0.27 g, 0.99 mmol) andtriethylamine (0.38 mL, 2.73 mmol), and the mixture was stirred at 25°C. for 16 hours. The reaction mixture was partitioned between ethylacetate and saturated NaHCO₃, and the organic phase was washed withbrine and dried over MgSO₄, filtered and concentrated. The residue waschromatographed on silica gel eluting 0-66% ethyl acetate in chloroformto give the title compound (0.080 g, 28% yield).

EXAMPLE 61B(2S)-3,3-dimethyl-2-{[(3-pyridinylmethoxy)carbonyl]amino}butanoic acid

A solution containing the product from Example 61A (0.017 g, 0.052 mmol)in dichloromethane (0.2 mL) was treated with trifluoroacetic acid (0.2mL), and the mixture was stirred at 25° C. for 2 hours. The solvent wasconcentrated and the residue was dissolved in toluene and concentratedseveral times to give the title compound as the trifluoroacetic acidsalt, which was used without further purification.

EXAMPLE 61C3-pyridinylmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate

A solution containing the product from Example 2C (0.025 g, 0.047 mmol)in THF (0.5 mL) was treated with the product from Example 61B (0.052mmol), DEPBT (0.021 g, 0.071 mmol), and N,N-diisopropylethylamine (0.041mL, 0.235 mmol) and the mixture was stirred at 25° C. for 16 hours. Themixture was partitioned between ethyl acetate and 10% Na₂CO₃ solution.The organic phase was washed with additional 10% Na₂CO₃ solution andbrine, dried over MgSO₄, filtered and concentrated. The residue waschromatographed on silica gel eluting with 0-5% methanol in chloroformto give the title compound (0.024 g, 65% yield). ¹H NMR (300 MHz,DMSO-d₆) δ ppm 0.79(m, 9H), 0.83(m, 9H), 1.59-1.46(m, 2H), 2.80-2.70(m,3H), 3.49(s, 3H), 3.69-3.60(m, 1H), 3.84-3.80(d, J=9.56 Hz, 1H),3.96-3.93(d, J=9.93Hz, 1H), 4.22-4.00(m, 2H), 4.88-4.86(d, J=5.52 Hz,1H), 5.14-5.04(m, 2H), 6.62-6.59(d, J=9.56 Hz, 1H), 7.03-7.00(d, J=9.93Hz, 1H), 7.20-7.06(m, 7H), 7.33-7.28(m, 1H), 7.43-7.39(m, 1H),7.59-7.56(d, J=9.19 Hz, 1H), 7.82-7.77(m, 2H), 7.89-7.84(m, 4H),8.54-8.53(m, 1H), 8.64-8.60(m, 2H).

EXAMPLE 62benzyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate

A solution containing the product from Example 58C (0.011 g, 0.014 mmol)in THF (0.2 mL) was treated with N-(benzyloxycarbonyloxy)succinimide(0.005 g, 0.020 mmol) and triethylamine (0.006 mL, 0.043 mmol) and themixture was stirred at 25° C. for 3 hours. The reaction was partitionedbetween ethyl acetate and saturated NaHCO₃, and the organic phase waswashed with brine and dried over MgSO₄, filtered and concentrated. Theresidue was chromatographed on silica gel eluting with 0-10% methanol inchloroform to give the title compound (0.006 g, 55% yield). ¹H NMR (300MHz, DMSO-d₆) δ ppm 0.80(m, 9H), 0.83(m, 9H), 1.59-1.46(m, 2H),2.80-2.70(m, 3H), 3.49(s, 3H), 3.69-3.60(m, 1H), 3.84-3.80(d, J=9.56 Hz,1H), 3.96-3.93(d, J=9.93 Hz, 1H), 4.22-4.00(m, 2H), 4.88-4.86(d, J=5.52Hz, 1H), 5.05(s, 2H), 6.62-6.58(d, J=9.56 Hz, 1H), 6.96-6.93(d, J=9.93Hz, 1H), 7.20-7.17(m, 8H), 7.38-7.29(m, 5H), 7.59-7.58(d, J=8.82 Hz,1H), 7.82-7.78(m, 1H), 7.89-7.84(m, 4H), 8.64-8.63(m, 1H).

EXAMPLE 63methyl(1S,4S,6S,7S,10S)-7-benzyl-1,10-ditert-butyl-6-hydroxy-13-methyl-2,9,12-trioxo-14-phenyl-4-[4-(2-pyridinyl)benzyl]-3,8,11,13-tetraazatetradec-1-ylcarbamateEXAMPLE 63Amethyl(2S)-3,3-dimethyl-2-{[(4-nitrophenoxy)carbonyl]amino}butanoate

A solution of L-tert-leucine methyl ester hydrochloride (0.300 g, 1.65mmol) in dichloromethane (4 mL) at 0° C. was treated with 4-nitrophenylchloroformate (0.366, 1.82 mmol) and N-methyl morpholine (0.380 mL, 3.46mmol), and the mixture was stirred at 25° C. for 64 hours. The reactionwas partitioned between dichloromethane and saturated NaHCO₃, and theorganic phase was washed with brine and dried over MgSO₄, filtered andconcentrated to give the title compound (0.562 g, quantitative), whichwas used without further purification.

EXAMPLE 63Bmethyl(2S)-2-({[benzyl(methyl)amino]carbonyl}amino)-3,3-dimethylbutanoate

A solution containing the product from Example 63A (0.075 g, 0.242 mmol)in toluene (0.5 mL) was treated with N-benzylmethylamine (0.035 mL, 2.71mmol), and the mixture was stirred at 80° C. for 1 hour. The reactionwas partitioned between ethyl acetate and 10% Na₂CO₃, and the organicphase was washed with brine and dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with0-20% ethyl acetate in dichloromethane to give the title compound (0.046g, 65% yield).

EXAMPLE 63C(2S)-2-({[benzyl(methyl)amino]carbonyl}amino)-3,3-dimethylbutanoic acid

A solution containing the product from Example 63B (0.046 g, 0.057 mmol)in dioxane (1.6 mL) was treated with an aqueous solution of lithiumhydroxide (0.63 mL, 0.5 N), and the mixture was stirred at 25° C. for 16hours. An aqueous HCl solution (0.60 mL, 1N) was added, the reactionmixture was partitioned between ethyl acetate and water, and the organicphase was washed with brine and dried over MgSO₄, filtered andconcentrated to give the crude product, which was used without furtherpurification.

EXAMPLE 63Dmethyl(1S,4S,6S,7S,10S)-7-benzyl-1,10-ditert-butyl-6-hydroxy-13-methyl-2,9,12-trioxo-14-phenyl-4-[4-(2-pyridinyl)benzyl]-3,8,11,13-tetraazatetradec-1-ylcarbamate

A solution containing the product from Example 2C (0.020 g, 0.038 mmol)in THF (0.4 mL) was treated with the product from Example 63C (0.013 g,0.047 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine(0.035 mL, 0.201 mmol) and the mixture was stirred at 25° C. for 45minutes. The mixture was partitioned between ethyl acetate and 10%Na₂CO₃ solution. The organic phase was washed with additional 10% Na₂CO₃solution and brine, dried over MgSO₄, filtered and concentrated. Theresidue was chromatographed on silica gel eluting with 0-100% ethylacetate/dichloromethane to give the title compound (0.017 g, 57% yield).¹H NMR (300 MHz, DMSO-d) δ ppm 0.80(s, 9H), 0.81(s, 9H), 1.58-1.49(m,2H), 2.74-2.72(m, 3H), 2.79(s, 3H), 3.49(s, 3H), 3.67-3.61(m, 1H),3.84-3.81(d, J=9.93 Hz, 1H), 4.12-3.99(m, 1H), 4.16-4.13(d, J=8.82 Hz,2H), 4.44(s, 2H), 4.82-4.80(d, J=5.88 Hz, 1H), 5.40-5.37(d, J=9.19 Hz,1H), 6.62-6.59(d, J=9.93 Hz, 1H), 7.35-7.10(m, 13H), 7.67-7.64(d, J=8.82Hz, 1H), 7.82-7.77(m, 1H), 7.88-7.84(m, 4H), 8.63 (d, J=4.41 Hz, 1 H).

EXAMPLE 64methyl(1S,4R,6S,7S,10S)-7-benzyl-1,10-ditert-butyl-6-hydroxy-13-methyl-2,9,12-trioxo-14-phenyl-4-[4-(2-pyridinyl)benzyl]-3,8,11,13-tetraazatetradec-1-ylcarbamate

A solution containing the product from Example 1H (0.020 g, 0.038 mmol)in THF (0.4 mL) was treated with the product from Example 63C (0.013 g,0.047 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine(0.035 mL, 0.201 mmol) and the mixture was stirred at 25° C. for 16hours. The mixture was partitioned between ethyl acetate and 10% Na₂CO₃solution. The organic phase was washed with additional 10% Na₂CO₃solution and brine, dried over MgSO₄, filtered and concentrated. Theresidue was chromatographed on silica gel eluting with 0-100% ethylacetate/dichloromethane to give the title compound (0.022 g, 74% yield).¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.75(m, 9H), 0.78(m, 9H), 1.35-1.22(m,1H), 1.65-1.54(m, 1H), 2.77-2.60(m, 4H), 2.79(s, 3H), 3.57(s, 3H),3.83-3.77(m, 1H), 3.94-3.83(m, 1H), 4.09-4.06(d, J=8.82 Hz, 1H),4.21-4.10(m, 1H), 4.51-4.38(m, 2H), 4.77-4.75(d, J=5.52 Hz, 1H),5.43-5.40(d, J=8.82 Hz, 1H), 6.85-6.82(d, J=9.52 Hz, 1H), 7.26-7.10(m,10H), 7.35-7.30(m, 1H). 3H), 7.60-7.57(d, J=9.19, 1H), 7.79-7.77(d,J=7.72 Hz, 1H), 7.93-7.82(m, 4H), 8.65-8.62(m, 1H).

EXAMPLE 65methyl(1S)-1-[({(1S,3S,4S)-4-({(2S)-3,3-dimethyl-2-[3-(2-methylbenzyl)-2-oxo-1-imidazolidinyl]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 65A(2S)-3,3-dimethyl-2-[3-(2-methylbenzyl)-2-oxo-1-imidazolidinyl]butanoicacid

A solution containing the product from Example 6F (0.150 g, 0.65 mmol)in a mixture of toluene (2.5 mL) and methanol (2.5 mL) was treated witho-tolualdehyde (0.081 mL, 0.687 mmol), and the mixture was stirred at50° C. for 18 hours. The reaction was cooled to 25° C. and sodiumborohydride (0.049 g, 1.29 mmol) was added and the reaction was stirredat 25° C. for 1 hour. The reaction mixture was quenched with 1N NaHCO₃,stirred for 1 hour, and partitioned between ethyl acetate and water. Theorganic phase was washed with brine and dried over MgSO₄, filtered andconcentrated. A solution containing the residue (0.220 g) in1,2-dichloroethane (10 mL) was treated with N,N-disuccinimidyl carbonate(0.20 g, 0.781 mmol) and triethylamine (0.11 mL, 0.789 mmol), stirred at25° C. for 68 hours, and partitioned with 10% Na₂CO₃, and the aqueouswas extracted with additional dichloromethane. The organic phase wasdried over MgSO₄, filtered and concentrated. A solution containing theconcentrate (0.245 g) in dichloromethane (2.5 mL) was treated withtrifluoracetic acid (2.5 mL), stirred at 25° C. for 2 hours andconcentrated to give the title compound, which was used without furtherpurification.

EXAMPLE 65Bmethyl(1S)-1-[({(1S,3S,4S)-4-({(2S)-3,3-dimethyl-2-[3-(2-methylbenzyl)-2-oxo-1-imidazolidinyl]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 2C (0.025 g, 0.047mmol)in THF (0.5 mL) was treated with the product from Example 65A(0.014 g, 0.046 mmol), DEPBT (0.021 g, 0.071 mmol), andN,N-diisopropylethylamine (0.041 mL, 0.235 mmol), stirred at 25° C. for16 hours, and partitioned between ethyl acetate and 10% Na₂CO₃ solution.The organic phase was washed with additional 10% Na₂CO₃ solution andbrine, dried over MgSO₄, filtered and concentrated. The residue waspurified by reversed phase chromatography on a C18 column eluting with5-100% acetonitrile in water (0.1% TFA). The product was partitionedbetween ethyl acetate and saturated NaHCO₃ solution. The organic phasewas washed brine, dried over MgSO₄, filtered and concentrated to givethe title compound (0.020 g, 49% yield). ¹H NMR (300 MHz, DMSO-d₆) δ ppm0.83(m, 9H), 0.89(m, 9H), 1.62-1.48(m, 2H), 2.31(s, 3H), 2.34-2.24(m,1H), 2.62-2.53(m, 1H), 2.68-2.65(m, 2H), 2.84-2.73(m, 2H), 2.97-2.88(m,1H), 3.22-3.12(m, 1H), 3.50(s, 3H), 3.70-3.62(m, 1H), 3.87-3.83(d,J=9.93 Hz, 1H), 4.08(s, 1H), 4.43-4.12(m, 4H), 4.55-4.52(d, J=7.72 Hz,1H), 6.65-6.62(d, J=9.56 Hz, 1H), 7.01-6.99(m, 3H), 7.09-7.08(m, 2H),7.24-7.20(m, 5H), 7.32-7.29(m, 1H), 7.49-7.46(d, J=9.56 Hz, 1H),7.91-7.82(m, 5H), 8.64-8.63(d, J=4.41 Hz, 1H).

EXAMPLE 66methyl(1S)-1-[({(1S,3S,4S)-4-({(2S)-3,3-dimethyl-2-[3-(3-methylbenzyl)-2-oxo-1-imidazolidinyl]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 66A(2S)-3,3-dimethyl-2-[3-(3-methylbenzyl)-2-oxo-1-imidazolidinyl]butanoicacid

A solution containing the product from Example 6F (0.150 g, 0.65 mmol)in a mixture of toluene (2.5 mL) and methanol (2.5 mL) was treated withm-tolualdehyde (0.080 mL, 0.692 mmol), stirred at 50° C. for 18 hours,cooled to 25° C., treated with sodium borohydride (0.049 g, 1.29 mmol),stirred at 25° C. for 1 hour, quenched with 1N NaHCO₃, stirred for 1hour, and partitioned between ethyl acetate and water. The organic phasewas washed with brine and dried over MgSO₄, filtered and concentrated. Asolution of the concentrate (0.211 g) in 1,2-dichloroethane (10 mL) wastreated with N,N-disuccinimidyl carbonate (0.20 g, 0.781 mmol) andtriethylamine (0.11 mL, 0.789 mmol), stirred at 25° C. for 68 hours, andpartitioned with 10% Na₂CO₃. The aqueous was extracted with additionalchloroform. The combined organic phase was dried over MgSO₄, filteredand concentrated. A solution of the concentrate (0.254 g) indichloromethane (2.5 mL) was treated with trifluoracetic acid (2.5 mL),and the mixture was stirred at 25° C. for 2 hours. The solvent wasconcentrated to give the title compound, which was used without furtherpurification.

EXAMPLE 66Bmethyl(1S)-1-[({(1S,3S,4S)-4-({(2S)-3,3-dimethyl-2-[3-(3-methylbenzyl)-2-oxo-1-imidazolidinyl]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 2C (0.025 g, 0.047 mmol)in THF (0.5 mL) was treated with the product from Example 66A (0.014 g,0.046 mmol), DEPBT (0.021 g, 0.071 mmol), and N,N-diisopropylethylamine(0.041 mL, 0.235 mmol) and the mixture was stirred at 25° C. for 16hours. The mixture was partitioned between ethyl acetate aid 10% Na₂CO₃solution. The organic phase was washed with additional 10% Na₂CO₃solution and brine, dried over MgSO₄, filtered and concentrated. Theproduct was purified by reversed phase chromatography on a C18 columneluting with 5-100% acetonitrile in water (0.1% TFA). The product waspartitioned between ethyl acetate and saturated NaHCO₃ solution. Theorganic phase was washed brine, dried over MgSO₄, filtered andconcentrated to give the title compound (0.018 g, 44% yield). ¹H NMR(300 MHz, DMSO-d₆) δ ppm 0.83(m, 9H), 0.89(m, 9H), 1.62-1.48(m, 2H),2.31(s, 3H), 2.34-2.24(m, 1H), 2.62-2.53(m, 1H), 2.68-2.65(m, 2H),2.97-2.73(m, 3H), 3.22-3.12(m, 1H), 3.50(s, 3H), 3.70-3.62(m, 1H),3.87-3.83(d, J=9.93 Hz, 1H), 4.08(s, 1H), 4.33-4.11(m, 4H), 4.56-4.53(d,J=7.72 Hz, 1H), 6.65-6.62(d, J=9.56 Hz, 1H), 7.04-7.02(m, 3H),7.11-7.07(m, 4H), 7.25-7.21(m, 4H), 7.33-7.28(m, 1H), 7.49-7.46(d,J=9.56 Hz, 1H), 7.91-7.82(m, 4H), 8.64-8.63(d, J=4.04 Hz, 1H).

EXAMPLE 67methyl(1S)-1-[({(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(2-methyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-phenyl-1-[4-(3-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 67Abenzyl(4S,5S)-5-{(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}-2,2-dimethyl-4-[4-(3-pyridinyl)benzyl]-1,3-oxazolidine-3-carboxylate

A solution containing the product from Example 23I(0.200 g, 0.283 mmol)in DMF (3 mL) was treated with LiCl (0.120 g, 2.83 mmol),dichlorobis(triphenylphosphine)palladium(II) (0.060 g, 0.085 mmol), and3-tri-n-butylstannylpyridine (0.200 mL, 0.870 mmol), heated at 100° C.for 16 hours, cooled and partitioned between ethyl acetate and water.The organic phase was washed with brine and dried over MgSO₄, filteredand concentrated. The residue was chromatographed on silica gel elutingwith 0-25% ethyl acetate in dichloromethane to give the title compound(0.130 g, 72% yield).

EXAMPLE 67Btert-butyl(1S,3S,4S)-4-amino-1-benzyl-3-hydroxy-5-[4-(3-pyridinyl)phenyl]pentylcarbamate

A solution containing the product from Example 67A (0.130 g, 0.205 mmol)in methanol (3 mL) was treated with Pd(OH)₂ on carbon (0.040 g, 20% Pdby wt.) and HCl solution (0.150 mL, 4N in dioxane), stirred under ahydrogen atmosphere (balloon pressure) for 2.5 hours at 25° C., filteredthrough a bed of celite® and rinsed with methanol. The filtrate wasconcentrated to give the title compound as the hydrochloride salt.

EXAMPLE 67Ctert-butyl(1S,3S,4S)-1-benzyl-3-hydroxy-4-({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-5-[4-(3-pyridinyl)phenyl]pentylcarbamate

A solution containing the product from Example 67B (0.205 mmol) in THF(2 mL) was treated with the product from Example 1F (0.046 g, 0.243mmol), DEPBT (0.10 g, 0.334 mmol), and N,N-diisopropylethylamine (0.350mL, 2.01 mmol), stirred at 25° C. for 16 hours, and partitioned betweenethyl acetate and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated to give the title compound (0.073 g), which was usedwithout further purification.

EXAMPLE 67Dmethyl(1S)-1-[({(1S,2S,4S)-4-amino-2-hydroxy-5-phenyl-1-[4-(3-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 67C (0.073 g) indichloromethane (5 mL) was treated with trifluoroacetic acid (5 mL) andthe mixture was stirred at 25° C. for 1 hour. The solvent wasconcentrated and the residue was purified by reversed phasechromatography on a C18 column eluting with 5-100% acetonitrile in water(0.1% TFA) to give the title compound as the trifluoroacetic acid salt(0.073 g, 47% yield).

EXAMPLE 67Emethyl(1S)-1-[({(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(2-methyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-phenyl-1-[4-(3-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 67D (0.025 g, 0.033 mmol)in THF (0.4 mL) was treated with the product from Example 14B (0.017 g,0.039 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine(0.060 mL, 0.344 mmol), stirred at 25° C. for 16 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was chromatographed on silica geleluting with 0-100% ethyl acetate/dichloromethane, followed by 0-5%methanol in ethyl acetate to give the title compound (0.01 g). ¹H NMR(300 MHz, DMSO-d₆), δ ppm 0.81 (s, 9 H), 0.86 (s, 9 H), 1.53 (m, 2 H),2.39 (m, 2 H), 2.66 (m, 4 H), 2.77 (d, J=6.99 Hz, 2 H), 3.00 (m, 2 H),3.19 (m, 1 H), 3.49 (s, 3 H), 3.61 (m, 1 H), 3.93 (m, 2 H), 4.32 (m, 4H), 4.83 (d, J=5.15 Hz, 1 H), 6.81 (d, J=9.19 Hz, 1 H), 7.03 (m, 5 H),7.21 (s, 1 H), 7.32 (d, J=8.09 Hz, 2 H), 7.46 (dd, J=7.72, 4.78 Hz, 1H), 7.55 (m, 3 H), 7.87 (d, J=8.82 Hz, 1 H), 8.01 (d, J=8.09 Hz, 1 H),8.53 (d, J=4.41 Hz, 1 H), 8.83 (d, J=1.84 Hz, 1 H).

EXAMPLE 68methyl(1S)-1-[({(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-1-[4-(6-methyl-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 68A 2-methyl-6-(tributylstannyl)pyridine

A solution containing 2-bromo-6-methylpyridine (1.48 g, 8.63 mmol) inether (15 mL) at −78° C. was treated with n-butyllithium (5.39 mL, 1.6 Min hexanes) dropwise, stirred at −78° C. for 1 hour, treated withtributyltin chloride (4.21 mL, 12.94 mmol), stirred at −78° C. for 4hours, quenched with saturated ammonium chloride solution, andpartitioned between ether and water. The organic phase was washed withbrine and dried over MgSO₄, filtered and concentrated. The residue waspurified by chromatography on neutral alumina eluting with 10% ethylacetate in dichloromethane to give the title compound.

EXAMPLE 68Bbenzyl(4S,5S)-5-{(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}-2,2-dimethyl-4-[4-(6-methyl-2-pyridinyl)benzyl]-1,3-oxazolidine-3-carboxylate

A solution containing the product from Example 23I (0.113 g, 0.160 mmol)in DMF (1.5 mL) was treated with LiCl (0.068 g, 1.60 mmol),dichlorobis(triphenylphosphine)palladium(II) (0.034 g, 0.048 mmol), andthe product from Example 68A (0.367 g, 0.961 mmol), heated at 110° C.for 16 hours, cooled and partitioned between ethyl acetate and water.The organic phase was washed with brine and dried over MgSO₄, filteredand concentrated. The residue was chromatographed on silica gel elutingwith 0-50% ethyl acetate in dichloromethane to give the title compound(0.102 g, 98% yield).

EXAMPLE 68Cbenzyl(1S,2S,4S)-4-amino-2-hydroxy-1-[4-(6-methyl-2-pyridinyl)benzyl]-5-phenylpentylcarbamate

A solution containing the product from Example 68B (0.07 g, 0.108 mmol)in a mixture of THF (0.5 mL), methanol (0.3 mL), and aqueous HCl (0.5mL, 1 N) was stirred at 50° C. for 16 hours. The solvent was removedunder reduced pressure to give the title compound as the hydrochloridesalt, which was used without further purification.

EXAMPLE 68Dbenzyl(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-1-[4-(6-methyl-2-pyridinyl)benzyl]-5-phenylpentylcarbamate

A solution containing the product from Example 68C (0.108 mmol) in THF(0.5 mL) was treated with the product from Example 10D (0.048 g, 0.14mmol), DEPBT (0.048 g, 0.162 mmol), and N,N-diisopropylethylamine (0.281mL, 1.62 mmol), stirred at 25° C. for 3 hours, and partitioned betweenethyl acetate and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with0-100% ethyl acetate/dichloromethane, followed by 0-5% methanol in ethylacetate to give the title compound (0.048 g, 56% yield).

EXAMPLE 68E(2S)-N-{(1S,3S,4S)-4-amino-1-benzyl-3-hydroxy-5-[4-(6-methyl-2-pyridinyl)phenyl]pentyl}-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanamide

A solution containing the product from Example 68D (0.046 g, 0.058 mmol)in a mixture of ethyl acetate (0.25 mL) and methanol (0.25 mL) wastreated with Pd(OH)₂ on carbon (0.012 g, 20% Pd by wt.) and HCl solution(0.058 mL, 4N in dioxane), stirred under a hydrogen atmosphere (balloonpressure) at 25° C. for 16 hours, filtered through a bed of celite® andrinsed with methanol. The solvent was concentrated to give the crudeproduct as the hydrochloride salt, which was used without furtherpurification.

EXAMPLE 68Fmethyl(1S)-1-[({(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-1-[4-(6-methyl-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 68E (0.058 mmol) in THF(0.5 mL) was treated with the product from Example 1F (0.013 g, 0.069mmol), DEPBT (0.026 g, 0.087 mmol), and N,N-diisopropylethylamine (0.100mL, 0.577 mmol), stirred at 25° C. for 16 hours, and partitioned betweenethyl acetate and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was purified by chromatography on silica geleluting with 0-100% ethyl acetate/dichloromethane, followed by 0-5%methanol in ethyl acetate, to give the title compound (0.033 g, 69%yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.84 (s, 9 H), 0.87 (s, 9 H),1.53 (m, 3 H), 2.42 (m, 5 H), 2.74 (m, 4 H), 3.05 (m, 2 H), 3.24 (m, 2H), 3.60 (m, 4 H), 3.97 (m, 2 H), 4.19 (m, 2 H), 4.34 (m, 2 H), 4.81 (d,J=5.15 Hz, 1 H), 6.78 (d, J=9.19 Hz, 1 H), 7.02 (m, 6 H), 7.16 (m, 2 H),7.29 (d, J=8.09 Hz, 2 H), 7.69 (m, 4 H), 7.89 (d, J=8.09 Hz, 3 H).

EXAMPLE 69methyl(1S)-1-[({(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-phenyl-1-[4-(3-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 67D (0.025 g, 0.033 mmol)in THF (0.4 mL) was treated with the product from Example 10D (0.016 g,0.047 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine(0.060 mL, 0.344 mmol), stirred at 25° C. for 16 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was chromatographed on silica geleluting with 0-100% ethyl acetate/dichloromethane, followed by elutionwith 0.5% methanol in ethyl acetate to give the title compound (0.015 g,56% yield). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.84(s, 9H), 0.86(s, 9H),1.59-1.50(m, 2H), 2.48-2.35(m, 2H), 2.46(s, 3H), 2.70-2.62(m, 1H),2.79-2.77(m, 2H), 3.00-2.92(m, 1H), 3.13-3.02(m, 1H), 3.28-3.18(m, 1H),3.49(s, 3H), 3.67-3.58(m, 1H), 3.95-3.93(m, 1H), 3.97(s, 1H),4.27-4.12(m, 2H), 4.40-4.26(m, 2H), 4.84-4.82(d, J=5.52 Hz, 1H),6.83-6.80 (d, J=9.56 Hz, 1H), 7.05-7.02 (m, 5H), 7.16-7.14(d, J=7.72 Hz,1H), 7.34-7.33(d, J=8.09 Hz, 2H), 7.49-7.44(dd, J=8.27, 4.96 Hz, 1H),7.59-7.53(m, 3H), 7.70-7.65(t, J=7.54 Hz, 1H), 7.91-7.88(d, J=9.19 Hz,1H), 8.03-7.99(m, J=6.07, 2.39 Hz, 1H), 8.55-8.53(dd, J=4.78, 1.47 Hz,1H), 8.84-8.83(d, J=1.84 Hz, 1H).

EXAMPLE 70methyl(1S)-1-[({(1S,2S,4S)-4-{[(2S)-2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-2-hydroxy-5-phenyl-1-[4-(3-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 70A(2S)-2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoic acid

A solution containing the product from Example 6F (1.0 g, 4.35 mmol) ina mixture of benzene (10 mL) and ethanol (10 mL) was treated withbenzaldehyde (0.46 mL, 4.55 mmol), stirred at 70° C. for 16 hours,cooled to 25° C., treated with sodium borohydride (0.50 g, 13.22 mmol),stirred at 25° C. for 3 hours, quenched with 1N NaHCO₃ and stirred for 1hour, and partitioned between ethyl acetate and saturated NaHCO₃. Theorganic phase was washed with brine and dried over MgSO₄, filtered andconcentrated. A solution of the concentrate (4.35 mmol) in1,2-dichloroethane (175 mL) was treated with N,N-disuccinimidylcarbonate (1.34 g, 5.23 mmol) and triethylamine (0.60 mL, 4.30 mmol),stirred at 25° C. for 16 hours, and partitioned with 10% Na₂CO₃. Theaqueous was extracted with additional dichloromethane. The combinedorganic phase was dried over MgSO₄, filtered and concentrated. Asolution of the concentrate (4.35 mmol) in dichloromethane (25 mL) wastreated with trifluoracetic acid (25 mL), and the mixture was stirred at25° C. for 2 hours. The solvent was concentrated, and the residue waspurified by reversed phase chromatography on a C18 column eluting with agradient starting with 0-100% acetonitrile/water (0.1% TFA) to give thetitle compound (0.76 g, 60% yield).

EXAMPLE 70Bmethyl(1S)-1-[({(1S,2S,4S)-4-{[(2S)-2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-2-hydroxy-5-phenyl-1-[4-(3-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 67D (0.025 g, 0.033 mmol)in THF (0.4 mL) was treated with the product from Example 70A (0.014 g,0.048 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine(0.060 mL, 0.344 mmol), stirred at 25° C. for 16 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was chromatographed on silica geleluting with 0-100% ethyl acetate/dichloromethane, followed by elutionwith 0.5% methanol in ethyl acetate to give the title compound (0.013 g,49% yield). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.83(s, 9H), 0.86(s, 9H),1.58-1.49(m, 2H), 2.45-2.35(m, 2H), 2.70-2.60(m, 1H), 2.99-2.74(m, 4H),3.24-3.15(m, 1H), 3.49(s, 3H), 3.67-3.58(m, 1H), 3.96-3.93(d, J=9.93 Hz,1H), 3.97(s, 1H), 4.27-4.11(m, 2H), 4.30(s, 2H), 4.84-4.82(d, J=5.88 Hz,1H), 6.83-6.80(d, J=9.19 Hz, 1H), 7.06-7.03(m, 5H), 7.40-7.25(m, 6H),7.49-7.44(dd, J=8.27, 4.96 Hz, 1H), 7.58-7.52(m, 3H), 7.91-7.88(d,J=8.82 Hz, 1H), 8.03-7.99(m, 1H), 8.55-8.52(dd, J=4.78, 1.47 Hz, 1H),8.84-8.83(d, J=2.21 Hz, 1H).

EXAMPLE 71methyl(1S)-1-[({(1S,3S,4S)-3-hydroxy-4-({(2S)-2-[3-(3-methoxybenzyl)-2-oxo-1-imidazolidinyl]-3,3-dimethylbutanoyl}amino)-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 71A(2S)-2-[3-(3-methoxybenzyl)-2-oxo-1-imidazolidinyl]-3,3-dimethylbutanoicacid

A solution containing the product from Example 6F (0.150 g, 0.65 mmol)in a mixture of toluene (2.5 mL) and methanol (2.5 mL) was treated withm-anisaldehyde (0.083 mL, 0.68 mmol), stirred at 50° C. for 18 hours,cooled to 25° C., treated with sodium borohydride (0.049 g, 1.29 mmol),stirred at 25° C. for 1 hour, quenched with 1N NaHCO₃ and stirred for 1hour, and partitioned between ethyl acetate and water. The organic phasewas washed with brine and dried over MgSO₄, filtered and concentrated. Asolution of the concentrate (0.242 g) in 1,2-dichloroethane (10 mL) wastreated with N,N-disuccinimidyl carbonate (0.20 g, 0.781 mmol) andtriethylamine (0.11 mL, 0.789 mmol), stirred at 25° C. for 68 hours, andpartitioned with 10% Na₂CO₃. The aqueous was extracted with additionalchloroform. The combined organic phase was dried over MgSO₄, filteredand concentrated. A solution of the concentrate (0.265 g) indichloromethane (2.5 mL) was treated with trifluoracetic acid (2.5 mL),stirred at 25° C. for 2 hours, and concentrated to give the titlecompound, which was used without further purification.

EXAMPLE 71Bmethyl(1S)-1-[({(1S,3S,4S)-3-hydroxy-4-({(2S)-2-[3-(3-methoxybenzyl)-2-oxo-1-imidazolidinyl]-3,3-dimethylbutanoyl}amino)-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 2C (0.025 g, 0.047 mmol)in THF (0.5 mL) was treated with the product from Example 71A (0.020 g,0.062 mmol), DEPBT (0.021 g, 0.071 mmol), and N,N-diisopropylethylamine(0.041 mL, 0.235 mmol), stirred at 25° C. for 16 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was purified by reversed phasechromatography on a C18 column eluting with a gradient starting with5-100% acetonitrile in water (0.1% TFA). The product was partitionedbetween ethyl acetate and saturated NaHCO₃ solution. The organic phasewas washed brine, dried over MgSO₄, filtered and concentrated to givethe title compound (0.024 g, 59% yield). ¹H NMR (300 MHz, DMSO-d₆), δppm 0.83 (s, 9 H), 0.89 (s, 9 H), 1.55 (m, 2 H), 2.32 (m, 1 H), 2.80 (m,6 H), 3.18 (m, 1 H), 3.50 (s, 3 H), 3.65 (m, 1 H), 3.74 (s, 3 H), 3.85(d, J=9.93 Hz, 1 H), 4.20 (m, 5 H), 4.54 (d, J=7.72 Hz, 1 H), 6.63 (d,J=9.93 Hz, 1 H), 6.85 (m, 3 H), 7.08 (m, 5 H), 7.28 (m, 4 H), 7.48 (d,J=9.56 Hz, 1 H), 7.86 (m, 5 H), 8.63 (d, J=4.78 Hz, 1 H).

EXAMPLE 72methyl(1S)-1-[({(1R,3S,4S)-4-{[(2S)-2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 1H (0.040 g, 0.075 mmol)in THF (0.6 mL) was treated with the product from Example 70A (0.027 g,0.092 mmol), DEPBT (0.034 g, 0.114 mmol), and N,N-diisopropylethylamine(0.066 mL, 0.379 mmol), stirred at 25° C. for 16 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was chromatographed on silica geleluting with 0-100% ethyl acetate/dichloromethane, followed by elutionwith 0-5% methanol in ethyl acetate to give the title compound (0.045 g,73% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.80 (s, 9 H), 0.87 (s, 9H), 1.38 (t, J=11.58 Hz, 1 H), 1.54 (m, 1 H), 2.41 (m, 1 H), 2.64 (m, 3H), 2.87 (m, 3 H), 3.19 (m, 1 H), 3.53 (m, 4 H), 3.84 (d, J=9.56 Hz, 1H), 3.95 (m, 1 H), 4.04 (s, 1 H), 4.18 (m, 1 H), 4.29 (m, 2 H), 4.45 (d,J=7.35 Hz, 1 H), 6.88 (d, J=9.56 Hz, 1 H), 7.05 (m, 5 H), 7.30 (m, 8 H),7.53 (d, J=9.56 Hz, 1 H), 7.90 (m, 5 H), 8.65 (d, J=4.41 Hz, 1 H).

EXAMPLE 73methyl(1S)-1-[({(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-phenyl-1-[4-(4-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 73Abenzyl(4S,5S)-5-{(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}-2,2-dimethyl-4-[4-(4-pyridinyl)benzyl]-1,3-oxazolidine-3-carboxylate

A solution containing the product from Example 23I (0.64 g, 0.906 mmol)in DMF (10 mL) was treated with LiCl (0.384 g, 9.06 mmol),dichlorobis(triphenylphosphine)palladium(II) (0.19 g, 0.271 mmol), and4(tri-n-butylstannyl)pyridine (1.0 g, 2.72 mmol), heated at 100° C. for16 hours, cooled and partitioned between ethyl acetate and water. Theorganic phase was washed with brine and dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with0-25% ethyl acetate in dichloromethane to give the title compound (0.28g, 49% yield).

EXAMPLE 73Bbenzyl(1S,2S,4S)-4-amino-2-hydroxy-5-phenyl-1-[4-(4-pyridinyl)benzyl]pentylcarbamate

A solution containing the product from Example 73A (0.28 g, 0.441 mmol)in a mixture of THF (5 mL), methanol (5 mL), and aqueous HCl (5 mL, 1 N)was stirred at 60° C. for 16 hours, and concentrated to give the titlecompound as the hydrochloride salt, which was used without furtherpurification.

EXAMPLE 73Cbenzyl(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-phenyl-1-[4-(4-pyridinyl)benzyl]pentylcarbamate

A solution containing the product from Example 73B (0.441 mmol) in THF(4.5 mL) was treated with the product from Example 10D (0.18 g, 0.526mmol), DEPBT (0.20 g, 0.669 mmol), and N,N-diisopropylethylamine (0.75mL, 4.31 mmol), stirred at 25° C. for 16 hours, and partitioned betweenethyl acetate and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with0-100% ethyl acetate/dichloromethane, followed by 7.5% methanol in ethylacetate to give the title compound (0.095 g, 28% yield).

EXAMPLE 73D(2S)-N-{(1S,3S,4S)-4-amino-1-benzyl-3-hydroxy-5-[4-(4-pyridinyl)phenyl]pentyl}-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanamide

A solution containing the product from Example 73C (0.095 g, 0.121 mmol)in methanol (1.5 mL) was treated with Pd(OH)₂ on carbon (0.075 g, 20% Pdby wt.) and HCl solution (0.090 mL, 4N in dioxane), stirred under ahydrogen atmosphere (balloon pressure) at 25° C. for 16 hours, filteredthrough a bed of celite® and rinsed with methanol. The solvent wasconcentrated to give the title compound as the hydrochloride salt, whichwas used without further purification.

EXAMPLE 73Emethyl(1S)-1-[({(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-phenyl-1-[4-(4-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 73D (0.121 mmol) in THF(1.2 mL) was treated with the product from Example 1F (0.030 g, 0.159mmol), DEPBT (0.055 g, 0.184 mmol), and N,N-diisopropylethylamine (0.225mL, 2.35 mmol), stirred at 25° C. for 4 hours, and partitioned betweenethyl acetate and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was purified by chromatography on silica geleluting with 0-100% ethyl acetate/dichloromethane, followed by 0-10%methanol in ethyl acetate, to give the title compound (0.048 g, 48%yield). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.83(s, 9H), 0.86(s, 9H),1.59-1.50(m, 2H), 2.48-2.35(m, 2H), 2.46(s, 3H), 2.70-2.62(m, 1H),2.79-2.77(m, 2H), 3.00-2.92(m, 1H), 3.13-3.02(m, 1H), 3.28-3.18(m, 1H),3.49(s, 3H), 3.67-3.58(m, 1H), 3.95-3.93(m, 1H), 3.97(s, 1H),4.27-4.12(m, 2H), 4.40-4.26(m, 2H), 4.84-4.82(m, 1H), 6.83-6.80(d,J=9.93 Hz, 1H), 7.09-7.00(m, 5H), 7.16-7.14(d, J=7.35 Hz, 1H),7.36-7.33(d, J=8.09 Hz, 2H), 7.74-7.53(m, 6H), 7.92-7.89(d, J=9.19 Hz,1H), 8.62-8.60(d, J=5.88 Hz, 2H).

EXAMPLE 74methyl(1S)-1-[({(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-1-[4-(5-methyl-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 74A 5-methyl-2-(tributylstannyl)pyridine

A solution containing 2-bromo-5-methylpyridine (1.42 g, 8.23 mmol) inether (15 mL) at −78° C. was treated with n-butyllithium (5.14 mL, 1.6 Min hexanes) dropwise, stirred at −78° C. for 1 hour, treated withtributyltin chloride (3.35 mL, 12.35 mmol), stirred at 0° C. for 4hours, quenched with saturated ammonium chloride solution andpartitioned between ether and water. The organic phase was washed withbrine and dried over MgSO₄, filtered and concentrated. The residue waspurified by chromatography on neutral alumina eluting with 10% ethylacetate in dichloromethane to give the title compound.

EXAMPLE 74Bbenzyl(4S,5S)-5-{(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}-2,2-dimethyl-4-[4-(5-methyl-2-pyridinyl)benzyl]-1,3-oxazolidine-3-carboxylate

A solution containing the product from Example 23I (0.114 g, 0.162 mmol)in DMF (1.6 mL) was treated with LiCl (0.068 g, 1.60 mmol),dichlorobis(triphenylphosphine)palladium(II) (0.034 g, 0.048 mmol), andthe product from Example 74A (0.367 g, 0.961 mmol), heated at 100° C.for 16 hours, cooled and partitioned between ethyl acetate and water.The organic phase was washed with brine and dried over MgSO₄, filteredand concentrated. The residue was chromatographed on silica gel elutingwith 0-15% ethyl acetate in dichloromethane. The product was purified byreversed phase chromatography on a C18 column eluting with 5-100%acetonitrile in water (0.1% TFA) to give the title compound (0.044 g,42% yield).

EXAMPLE 74Cbenzyl(1S,2S,4S)-4-amino-2-hydroxy-1-[4-(5-methyl-2-pyridinyl)benzyl]-5-phenylpentylcarbamate

A solution containing the product from Example 74B (0.044 g, 0.068 mmol)in a mixture of THF (0.3 mL), methanol (0.2 mL), and aqueous HCl (0.4mL, 1 N) was stirred at 50° C. for 16 hours. The solvent was removedunder reduced pressure to give the title compound as the hydrochloridesalt, which was used without further purification.

EXAMPLE 74Dbenzyl(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-1-[4-(5-methyl-2-pyridinyl)benzyl]-5-phenylpentylcarbamate

A solution containing the product from Example 74C (0.068 mmol) in THF(0.5 mL) was treated with the product from Example 10D (0.030 g, 0.088mmol), DEPBT (0.030 g, 0.102 mmol), and N,N-diisopropylethylamine (0.177mL, 1.02 mmol), stirred at 25° C. for 3 hours, and partitioned betweenethyl acetate and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with0-100% ethyl acetate/dichloromethane, followed by 0-5% methanol in ethylacetate to give the title compound (0.033 g, 61% yield).

EXAMPLE 74E(2S)-N-{(1S,3S,4S)-4-amino-1-benzyl-3-hydroxy-5-[4-(5-methyl-2-pyridinyl)phenyl]pentyl}-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanamide

A solution containing the product from Example 74D (0.033 g, 0.041 mmol)in a mixture of ethyl acetate (0.25 mL) and methanol (0.25 mL) wastreated with Pd(OH)₂ on carbon (0.009 g, 20% Pd by wt.) and HCl solution(0.041 mL, 4N in dioxane), stirred under a hydrogen atmosphere (balloonpressure) at 25° C. for 16 hours, filtered through a bed of celite® andrinsed with methanol. The solvent was concentrated to give the titlecompound as the hydrochloride salt, which was used without furtherpurification.

EXAMPLE 74Fmethyl(1S)-1-[({(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-1-[4-(5-methyl-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 74E (0.041 mmol) in THF(0.5 mL) was treated with the product from Example 1F (0.010 g, 0.053mmol), DEPBT (0.018 g, 0.061 mmol), and N,N-diisopropylethylamine (0.071mL, 0.408 mmol), stirred at 25° C. for 16 hours, and partitioned betweenethyl acetate and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was purified by chromatography on silica geleluting with 0-100% ethyl acetate/dichloromethane, followed by 0-5%methanol in ethyl acetate, to give the title compound (0.024 g, 70%yield). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.83(m, 9H), 0.86(m, 9H),1.60-1.47(m, 2H), 2.32(s, 3H), 2.46-2.39(m, 2H), 2.46(s, 3H),2.682.64(m, 1H), 2.78-2.76(d, J=6.62 Hz, 2H), 2.99-2.91(m, 1H),3.12-3.03(m, 1H), 3.27-3.18(m, 1H), 3.52(s, 3H), 3.65-3.57(m, 1H),3.96-3.94(m, 2H), 4.26-4.11(m, 2H), 4.40-4.28(m, 2H), 4.84-4.82(d,J=5.52 Hz, 1H), 6.81-6.78(d, J=9.93 Hz, 1H), 7.05-7.0(m, 5H),7.16-7.14(d, J=7.72 Hz, 1H), 7.30-7.27(d, J=8.09 Hz, 2H), 7.59-7.56(m, 1H), 7.70-7.65 (m, 2H), 7.79-7.77(d, J=8.46 Hz, 1H), 7.91-7.86(m, 3H)8.46(bs, 1H).

EXAMPLE 75methyl(1S)-1-[({(1S,3S,4S)-3-hydroxy-4-({(2S)-2-[3-(2-methoxybenzyl)-2-oxo-1-imidazolidinyl]-3,3-dimethylbutanoyl}amino)-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 75A(2S)-2-[3-(2-methoxybenzyl)-2-oxo-1-imidazolidinyl]-3,3-dimethylbutanoicacid

A solution containing the product from Example 6F (0.150 g, 0.65 mmol)in a mixture of toluene (2.5 mL) and methanol (2.5 mL) was treated witho-anisaldehyde (0.079 mL, 0.68 mmol), and the mixture was stirred at 50°C. for 18 hours. The reaction was cooled to 25° C. and sodiumborohydride (0.049 g, 1.29 mmol) was added and the reaction was stirredat 25° C. for 1 hour. The reaction was quenched with 1N NaHCO₃ andstirred for 1 hour. The reaction was partitioned between ethyl acetateand water, and the organic phase was washed with brine and dried overMgSO₄, filtered and concentrated. A solution of the concentrate (0.261g) in 1,2-dichloroethane (10 mL) was treated with N,N-disuccinimidylcarbonate (0.20 g, 0.781 mmol) and triethylamine (0.11 mL, 0.789 mmol),and the mixture was stirred at 25° C. for 18 hours. The reaction waspartitioned with 10% Na₂CO₃, and the aqueous was extracted withadditional chloroform. The organic phase was dried over MgSO₄, filteredand concentrated. A solution of the concentrate (0.319 g) indichloromethane (2.5 mL) was treated with trifluoracetic acid (2.5 mL),and the mixture was stirred at 25° C. for 1 hour. The solvent wasconcentrated to give the title compound (0.371 g), which was usedwithout further purification.

EXAMPLE 75Bmethyl(1S)-1-[({(1S,3S,4S)-3-hydroxy-4-({(2S)-2-[3-(2-methoxybenzyl)-2-oxo-1-imidazolidinyl]-3,3-dimethylbutanoyl}amino)-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 2C (0.025 g, 0.047 mmol)in THF (0.5 mL) was treated with the product from Example 75A (0.020 g,0.062 mmol), DEPBT (0.021 g, 0.071 mmol), and N,N-diisopropylethylamine(0.041 mL, 0.235 mmol) and the mixture was stirred at 25° C. for 2hours. The mixture was partitioned between ethyl acetate and 10% Na₂CO₃solution. The organic phase was washed with additional 10% Na₂CO₃solution and brine, dried over MgSO₄, filtered and concentrated. Theproduct was purified by reversed phase chromatography on a C18 columneluting with 5-100% acetonitrile in water (0.1% TFA). The product waspartitioned between ethyl acetate and saturated NaHCO₃ solution. Theorganic phase was washed brine, dried over MgSO₄, filtered andconcentrated to give the title compound (0.024 g, 59% yield). ¹H NMR(300 MHz, DMSO-d₆), δ ppm 0.83 (s, 9 H), 0.89 (s, 9 H), 1.26 (m, 1 H),1.38 (m, 1 H), 1.54 (m, 2 H), 2.33 (m, 1 H), 2.83 (m, 5 H), 3.18 (m, 1H), 3.50 (s, 3 H), 3.66 (m, 1 H), 3.83 (m, 4 H), 4.25 (m, 4 H), 4.53 (d,J=7.72 Hz, 1 H), 6.63 (d, J=9.93 Hz, 1 H), 6.95 (t, J=6.99 Hz, 1 H),7.18 (m, 11 H), 7.45 (d, J=9.19 Hz, 1 H), 7.86 (m, 5 H), 8.63 (d, J=4.41Hz, 1 H).

EXAMPLE 76methyl(1S)-1-[({(1R,3S,4S)-4-({(2S)-3,3-dimethyl-2-[3-(2-methylbenzyl)-2-oxo-1-imidazolidinyl]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 1H (0.020 g, 0.038mmol)in THF (0.4 mL) was treated with the product from Example 65A(0.023 g, 0.076 mmol), DEPBT (0.017 g, 0.057 mmol), andN,N-diisopropylethylamine (0.033 mL, 0.189 mmol) and the mixture wasstirred at 25° C. for 2 hours. The mixture was partitioned between ethylacetate and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The product was purified by reversed phase chromatographyon a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA).The product was partitioned between ethyl acetate and saturated NaHCO₃solution. The organic phase was washed brine, dried over MgSO₄, filteredand concentrated to give the title compound (0.013 g, 42% yield). ¹H NMR(300 MHz, DMSO-d₆), δ ppm 0.80 (s, 9 H), 0.89 (m, 9 H), 1.46 (m, 2 H),2.29 (s, 3 H), 2.38 (m, 1 H), 2.76 (m, 5 H), 3.22 (m, 2 H), 3.53 (m, 4H), 3.84 (d, J=9.93 Hz, 1 H), 3.95 (m, 1 H), 4.02 (s, 1 H), 4.18 (m, 2H), 4.41 (m, 2 H), 6.88 (d, J=9.56 Hz, 1 H), 7.04 (m, 5 H), 7.21 (m, 6H), 7.32 (m, 1 H), 7.53 (d, J=9.56 Hz, 1 H), 7.89 (m, 5 H), 8.65 (d,J=4.04 Hz, 1 H).

EXAMPLE 77methyl(1S)-1-[({(1R,3S,4S)-4-({(2S)-3,3-dimethyl-2-[3-(3-methylbenzyl)-2-oxo-1-imidazolidinyl]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 1H (0.020 g, 0.038 mmol)in THF (0.4 mL) was treated with the product from Example 66A (0.023 g,0.076 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine(0.033 mL, 0.189 mmol) and the mixture was stirred at 25° C. for 2hours. The mixture was partitioned between ethyl acetate and 10% Na₂CO₃solution. The organic phase was washed with additional 10% Na₂CO₃solution and brine, dried over MgSO₄, filtered and concentrated. Theresidue was purified by reversed phase chromatography on a C18 columneluting with 5-100% acetonitrile in water (0.1% TFA). The product waspartitioned between ethyl acetate and saturated NaHCO₃ solution. Theorganic phase was washed brine, dried over MgSO₄, filtered andconcentrated to give the title compound (0.013 g, 42% yield). ¹H NMR(300 MHz, DMSO-d₆), δ ppm 0.80 (s, 9 H), 0.89 (m, 9 H), 1.47 (m, 2 H),2.28 (s, 3 H), 2.39 (m, 1 H), 2.78 (m, 6 H), 3.22 (m, 1 H), 3.54 (m, 4H), 3.84 (d, J=9.93 Hz, 1 H), 3.93 (m, 1 H), 4.04 (s, 1 H), 4.25 (m, 3H), 4.45 (d, J=6.99 Hz, 1 H), 6.88 (d, J=9.93 Hz, 1 H), 7.05 (m, 7 H),7.24 (m, 4 H), 7.32 (m, 1 H), 7.54 (d, J=9.56 Hz, 1 H), 7.89 (m, 5 H),8.65 (d, J=4.41 Hz, 1 H).

EXAMPLE 78 methyl(1S)-1-[({(1R,3S,4S)-3-hydroxy-4-({(2S)-2-[3-(2-methoxybenzyl)-2-oxo-1-imidazolidinyl]-3,3-dimethylbutanoyl}amino)-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 1H (0.020 g, 0.038 mmol)in THF (0.4 mL) was treated with the product from Example 75A (0.018 g,0.056 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine(0.033 mL, 0.189 mmol), stirred at 25° C. for 2 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was purified by reversed phasechromatography on a C18 column eluting with 5-100% acetonitrile in water(0.1% TFA). The product was partitioned between ethyl acetate andsaturated NaHCO₃ solution. The organic phase was washed brine, driedover MgSO₄, filtered and concentrated to give the title compound (0.016g, 47% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.80 (s, 9 H), 0.89 (m,9 H), 1.26 (m, 1 H), 1.39 (m, 1 H), 1.54 (m, 1 H), 2.41 (m, 1 H), 2.65(m, 2 H), 2.89 (m, 3 H), 3.20 (m, 1 H), 3.54 (m, 4 H), 3.81 (m, 4 H),3.93 (m, 1 H), 4.02 (m, 1 H), 4.28 (m, 3 H), 4.44 (d, J=7.35 Hz, 1 H),6.91 (m, 2 H), 7.04 (m, 6 H), 7.14 (d, J=7.35 Hz, 1 H), 7.28 (m, 4 H),7.51 (d, J=9.93 Hz, 1 H), 7.90 (m, 5 H), 8.65 (d, J=4.04 Hz, 1 H).

EXAMPLE 79methyl(1S)-1-[({(1R,3S,4S)-3-hydroxy-4-({(2S)-2-[3-(3-methoxybenzyl)-2-oxo-1-imidazolidinyl]-3,3-dimethylbutanoyl}amino)-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 1H (0.020 g, 0.038 mmol)in THF (0.4 mL) was treated with the product from Example 71A (0.018 g,0.056 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine(0.033 mL, 0.189 mmol), stirred at 25° C. for 2 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was purified by reversed phasechromatography on a C18 column eluting with 5-100% acetonitrile in water(0.1% TFA). The product was partitioned between ethyl acetate andsaturated NaHCO₃ solution. The organic phase was washed brine, driedover MgSO₄, filtered and concentrated to give the title compound (0.018g, 54% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.80 (s, 9 H), 0.87 (s,9 H), 1.25 (m, 1 H), 1.39 (m, 1 H), 1.54 (m, 1 H), 2.42 (m, 1 H), 2.64(m, 3 H), 2.89 (m, 2 H), 3.21 (m, 1 H), 3.54 (m, 4 H), 3.72 (s, 3 H),3.84 (d, J=9.56 Hz, 1 H), 3.96 (m, 1 H), 4.04 (s, 1 H), 4.18 (m, 1 H),4.27 (s, 2 H), 4.44 (d, J=6.99 Hz, 1 H), 6.85 (m, 4 H), 7.06 (m, 5 H),7.29 (m, 4 H), 7.54 (d, J=9.56 Hz, 1 H), 7.89 (m, 5 H), 8.65 (d, J=4.41Hz, 1 H).

EXAMPLE 80methyl(1S)-1-[({(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-1-[4-(4-methyl-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 80A 4-methyl-2-(tributylstannyl)pyridine

A solution containing 2-bromo-4-methylpyridine (1.46 g, 8.49 mmol) inether (15 mL) at −78° C. was treated with n-butyllithium (5.57 mL, 1.6 Min hexanes) dropwise, stirred at −78° C. for 1 hour, treated withtributyltin chloride (3.45 mL, 12.74 mmol), stirred at 0° C. for 4hours, quenched with saturated ammonium chloride solution andpartitioned between ether and water. The organic phase was washed withbrine and dried over MgSO₄, filtered and concentrated. The residue waspurified by chromatography on neutral alumina eluting with 10% ethylacetate in dichloromethane to give the title compound.

EXAMPLE 80Bbenzyl(4S,5S)-5-{(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}-2,2-dimethyl-4-[4-(4-methyl-2-pyridinyl)benzyl]-1,3-oxazolidine-3-carboxylate

A solution containing the product from Example 23I (0.183 g, 0.259 mmol)in DMF (2.6 mL) was treated with LiCl (0.110 g, 2.59 mmol),dichlorobis(triphenylphosphine)palladium(II) (0.055 g, 0.078 mmol), andthe product from Example 80A (0.495 g, 1.29 mmol), heated at 100° C. for16 hours, cooled and partitioned between ethyl acetate and water. Theorganic phase was washed with brine and dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with0-10% ethyl acetate in dichloromethane, to give the title compound(0.065 g, 39% yield).

EXAMPLE 80Cbenzyl(1S,2S,4S)-4-amino-2-hydroxy-1-[4-(4-methyl-2-pyridinyl)benzyl]-5-phenylpentylcarbamate

A solution containing the product from Example 80B (0.065 g, 0.100 mmol)in a mixture of THF (0.3 mL), methanol (0.3 mL), and aqueous HCl (0.5mL, 1 N) was stirred at 50° C. for 16 hours. The solvent was removedunder reduced pressure to give the title compound as the hydrochloridesalt, which was used without further purification.

EXAMPLE 80Dbenzyl(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-1-[4-(4-methyl-2-pyridinyl)benzyl]-5-phenylpentylcarbamate

A solution of the product from Example 80C (0.100 mmol) in THF (1 mL)was treated with the product from Example 10D (0.044 g, 0.13 mmol),DEPBT (0.044 g, 0.15 mmol), and N,N-diisopropylethylamine (0.261 mL, 1.5mmol), stirred at 25° C. for 1.5 hours, and partitioned between ethylacetate and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with0-100% ethyl acetate/dichloromethane, followed by 0-3% methanol in ethylacetate to give the title compound (0.054 g, 68% yield).

EXAMPLE 80E(2S)-N-{(1S,3S,4S)-4-amino-1-benzyl-3-hydroxy-5-[4-(4-methyl-2-pyridinyl)phenyl]pentyl}-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanamide

A solution containing the product from Example 80D (0.054 g, 0.068 mmol)in a mixture of ethyl acetate (0.3 mL) and methanol (0.3 mL) was treatedwith Pd(OH)₂ on carbon (0.014 g, 20% Pd by wt.) and HCl solution (0.068mL, 4N in dioxane), stirred under a hydrogen atmosphere (balloonpressure) at 25° C. for 16 hours, filtered through a bed of celite® andrinsed with methanol. The solvent was concentrated to give the titlecompound as the hydrochloride salt, which was used without furtherpurification.

EXAMPLE 80Fmethyl(1S)-1-[({(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-1-[4-(4-methyl-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 80E (0.068 mmol) in THF(0.65 mL) was treated with the product from Example 1F (0.017 g, 0.088mmol), DEPBT (0.030 g, 0.102 mmol), and N,N-diisopropylethylamine (0.118mL, 0.678 mmol), stirred at 25° C. for 16 hours, and partitioned betweenethyl acetate and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was purified by chromatography on silica geleluting with 0-100% ethyl acetate/dichloromethane, followed by 0-5%methanol in ethyl acetate, to give the title compound (0.036 g, 64%yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.83 (s, 9 H), 0.86 (s, 9 H),1.53 (m, 2 H), 2.42 (m, 8 H), 2.73 (m, 3 H), 3.03 (m, 2 H), 3.23 (m, 1H), 3.52 (s, 3 H), 3.62 (m, 1 H), 3.94 (m, 2 H), 4.18 (m, 2 H), 4.34 (m,2 H), 4.83 (d, J=5.88 Hz, 1 H), 6.79 (d, J=9.56 Hz, 1 H), 7.05 (m, 6 H),7.16 (m, 2 H), 7.29 (d, J=8.09 Hz, 2 H), 7.58 (d, J=8.46 Hz, 1 H), 7.69(m, 2 H), 7.90 (d, J=8.46 Hz, 3 H), 8.48 (d, J=4.78 Hz, 1 H).

EXAMPLE 81methyl(1S)-1-[({(1S,2S,4S)-4-{[(2S)-2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-2-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 23S (0.020 g, 0.038 mmol)in THF (0.4 mL) was treated with the product from Example 70A (0.013 g,0.045 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine(0.039 mL, 0.224 mmol), stirred at 25° C. for 16 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was chromatographed on silica geleluting with 0-100% ethyl acetate/dichloromethane, followed by elutionwith 5% methanol in ethyl acetate to give the title compound (0.009 g,30% yield). ¹H NMR (300 MHz, CDCl₃), δ ppm 0.96 (s, 9 H), 1.00 (s, 9 H),1.27 (m, 1 H), 2.62 (dd, J=13.79, 8.64 Hz, 1 H), 2.85 (m, 5 H), 3.03 (q,J=8.58 Hz, 1 H), 3.39 (m, 1 H), 3.64 (m, 4 H), 3.82 (d, J=9.19 Hz, 1 H),3.94 (m, 1 H), 4.00 (s, 1 H), 4.11 (m, 2 H), 4.35 (m, 2 H), 5.31 (m, 1H), 6.13 (m, 2 H), 7.10 (m, 5 H), 7.21 (m, 2 H), 7.33 (m, 7 H), 7.74 (m,2 H), 7.89 (d, J=8.46 Hz, 2 H), 8.68 (d, J=4.78 Hz, 1 H).

EXAMPLE 82methyl(1S)-1-[({(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(2-methyl-3-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 82A(2S)-3,3-dimethyl-2-{3-[(2-methyl-3-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoicacid

A solution containing the product from Example 6F (0.150 g, 0.65 mmol)in a mixture of toluene (2.5 mL) and methanol (2.5 mL) was treated withthe product from Example 15A (0.079 mL, 0.65 mmol), stirred at 50° C.for 18 hours, cooled to 25° C., treated with sodium borohydride (0.049g, 1.29 mmol), stirred at 25° C. for 1 hour, quenched with 1N NaHCO₃,stirred for 1 hour, and partitioned between ethyl acetate and water. Theorganic phase was washed with brine and dried over MgSO₄, filtered andconcentrated. A solution of the concentrate (0.214 g) in1,2-dichloroethane (10 mL) was treated with N,N-disuccinimidyl carbonate(0.20 g, 0.781 mmol) and triethylamine (0.11 mL, 0.789 mmol), stirred at25° C. for 16 hours, and partitioned with 10% Na₂CO₃. The aqueous wasextracted with additional chloroform. The combined organic phase wasdried over MgSO₄, filtered and concentrated. A solution of theconcentrate (0.268 g) in dichloromethane (2.5 mL) was treated withtrifluoracetic acid (2.5 mL), and the mixture was stirred at 25° C. for2 hours. The solvent was concentrated to give the title compound (0.430g) as the trifluoroacetic acid salt, which was used without furtherpurification.

EXAMPLE 82Bmethyl(1S)-1-[({(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(2-methyl-3-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 2C (0.020 g, 0.038 mmol)in THF (0.4 mL) was treated with the product from Example 82A (0.025 g,0.082 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine(0.033 mL, 0.189 mmol) and the mixture was stirred at 25° C. for 16hours. The mixture was partitioned between ethyl acetate and 10% Na₂CO₃solution. The organic phase was washed with additional 10% Na₂CO₃solution and brine, dried over MgSO₄, filtered and concentrated. Theresidue was purified by reversed phase chromatography on a C18 columneluting with 5-100% acetonitrile in water (0.1% TFA). The product waspartitioned between ethyl acetate and saturated NaHCO₃ solution. Theorganic phase was washed brine, dried over MgSO₄, filtered andconcentrated to give the title compound (0.016 g, 52% yield). ¹H NMR(300 MHz, DMSO-d₆), δ ppm 0.83 (s, 9 H), 0.89 (s, 9 H), 1.26 (m, 2 H),1.54 (m, 2 H), 2.32 (m, 1 H), 2.61 (m, 4 H), 2.81 (m, 2 H), 2.96 (q,J=8.95 Hz, 1 H), 3.21 (m, 1 H), 3.50 (s, 3 H), 3.66 (m, 1 H), 3.85 (d,J=9.93 Hz, 1 H), 4.08 (s, 1 H), 4.21 (m, 3 H), 4.42 (m, 1 H), 4.55 (d,J=7.72 Hz, 1 H), 6.65 (d, J=9.93 Hz, 1 H), 7.00 (m, 3 H), 7.10 (m, 2 H),7.24 (m, 3 H), 7.31 (m, 1 H), 7.54 (m, 2 H), 7.87 (m, 5 H), 8.38 (dd,J=4.78, 1.47 Hz, 1 H), 8.64 (d, J=4.41 Hz, 1 H).

EXAMPLE 83methyl(1S)-1-[({(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-3-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 83A(2S)-3,3-dimethyl-2-{3-[(6-methyl-3-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoicacid

A solution containing the product from Example 6F (0.150 g, 0.65 mmol)in a mixture of toluene (2.5 mL) and methanol (2.5 mL) was treated withthe product from Example 13A (0.079 mL, 0.65 mmol), stirred at 50° C.for 16 hours, cooled to 25° C., treated with sodium borohydride (0.049g, 1.29 mmol), stirred at 25° C. for 1 hour, quenched with 1N NaHCO₃ andstirred for 1 hour, and partitioned between ethyl acetate and water. Theorganic phase was washed with brine and dried over MgSO₄, filtered andconcentrated. A solution of the concentrate (0.194 g) in1,2-dichloroethane (10 mL) was treated with N,N-disuccinimidyl carbonate(0.20 g, 0.781 mmol) and triethylamine (0.11 mL, 0.789 mmol), stirred at25° C. for 16 hours, and partitioned with 10% Na₂CO₃. The aqueous wasextracted with additional chloroform. The combined organic phase wasdried over MgSO₄, filtered and concentrated. A solution of theconcentrate (0.223 g) in dichloromethane (2.5 mL) was treated withtrifluoracetic acid (2.5 mL), and the mixture was stirred at 25° C. for2 hours. The solvent was concentrated to give the title compound (0.379g) as the trifluoroacetic acid salt, which was used without furtherpurification.

EXAMPLE 83Bmethyl(1S)-1-[({(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-3-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 2C (0.020 g, 0.038 mmol)in THF (0.4 mL) was treated with the product from Example 83A (0.025 g,0.082 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine(0.033 mL, 0.189 mmol), stirred at 25° C. for 16 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was purified by reversed phasechromatography on a C18 column eluting with 5-100% acetonitrile in water(0.1% TFA). The product was partitioned between ethyl acetate andsaturated NaHCO₃ solution. The organic phase was washed brine, driedover MgSO₄, filtered and concentrated to give the title compound (0.014g, 45% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.83 (s, 9 H), 0.88 (s,9 H), 1.25 (m, 1 H), 1.54 (m, 2 H), 2.32 (m, 1 H), 2.45 (s, 3 H), 2.63(m, 2 H), 2.89 (m, 3 H), 3.18 (m, 1 H), 3.50 (s, 3 H), 3.66 (m, 1 H),3.85 (d, J=9.93 Hz, 1 H), 4.13 (m, 3 H), 4.30 (s, 2 H), 4.55 (d, J=7.35Hz 1 H), 6.65 (d, J=9.56 Hz, 1 H), 7.07 (m, 5 H), 7.28 (m, 4 H), 7.54(m, 2 H), 7.86 (m, 5 H), 8.37 (d, J=1.84 Hz, 1 H), 8.63 (d, J=4.41 Hz, 1H).

EXAMPLE 84methyl(1S)-1-[({(1S,3S,4S)-4-({(2S)-3,3-dimethyl-2-[2-oxo-3-(3-pyridinylmethyl)-1-imidazolidinyl]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 2C (0.015 g, 0.028 mmol)in THF (0.3 mL) was treated with the product from Example 20A (0.019 g,0.047 mmol), DEPBT (0.013 g, 0.043 mmol), and N,N-diisopropylethylamine(0.025 mL, 0.144 mmol), stirred at 25° C. for 16 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was purified by reversed phasechromatography on a C18 column eluting with 5-100% acetonitrile in water(0.1% TFA). The product was partitioned between ethyl acetate andsaturated NaHCO₃ solution. The organic phase was washed brine, driedover MgSO₄, filtered and concentrated to give the title compound (0.013g, 55% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.83 (s, 9 H), 0.88 (s,9 H), 126 (m, 1 H), 1.54 (m, 2 H), 2.32 (m, 1 H), 2.77 (m, 5 H), 3.18(m, 1 H), 3.50 (s, 3 H), 3.66 (m, 1 H), 3.85 (d, J=9.93 Hz, 1 H), 4.28(m, 5 H), 4.55 (d, J=7.72 Hz, 1 H), 6.65 (d, J=9.93 Hz, 1 H), 7.03 (m, 2H), 7.10 (m, 2 H), 7.22 (d, J=8.46 Hz, 2 H), 7.31 (m, 1 H), 7.41 (dd,J=7.72, 5.15 Hz, 1 H), 7.51 (d, J=9.56 Hz, 1 H), 7.68 (m, 1 H), 7.86 (m,6 H), 8.52 (m, 2 H), 8.63 (d, J=4.41 Hz, 1 H).

EXAMPLE 85methyl(1S)-1-[({(1S,3S,4S)-4-({(2S)-3,3-dimethyl-2-[2-oxo-3-(4-pyridinylmethyl)-1-imidazolidinyl]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 85A(2S)-3,3-dimethyl-2-[2-oxo-3-(4-pyridinylmethyl)-1-imidazolidinyl]butanoicacid

A solution containing the product from Example 6F (0.10 g, 0.43 mmol) ina mixture of benzene (1.6 mL) and methanol (1.66 mL) was treated withpyridine-4-carboxaldehyde (0.041 mL, 0.43 mmol), stirred at 50° C. for18 hours, cooled to 25° C., treated with sodium borohydride (0.033 g,0.87 mmol), stirred at 25° C. for 1 hour, quenched with saturatedNaHCO₃, stirred for 1 hour, and partitioned between ethyl acetate andsaturated NaHCO₃. The organic phase was washed with brine and dried overMgSO₄, filtered and concentrated. A solution of the concentrate (0.43mmol) in 1,2-dichloroethane (7 mL) was treated with N,N-disuccinimidylcarbonate (0.134 g, 0.52 mmol) and triethylamine (0.07 mL, 0.50 mmol),and the mixture was stirred at 25° C. for 16 hours. The reaction wasdiluted with chloroform and partitioned with 10% Na₂CO₃. The organicphase was washed with brine, dried over MgSO₄, filtered andconcentrated. A solution containing the resulting residue (0.43 mmol) indichloromethane (2 mL) was treated with trifluoracetic acid (2 mL), andthe mixture was stirred at 25° C. for 2 hours. The solvent wasconcentrated, and the product was dissolved in toluene and concentratedseveral times to give the title compound (0.259 g), as thetrifluoroacetic acid salt.

EXAMPLE 85Bmethyl(1S)-1-[({(1S,3S,4S)-4-({(2S)-3,3-dimethyl-2-[2-oxo-3-(4-pyridinylmethyl)-1-imidazolidinyl]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 2C (0.015 g, 0.028 mmol)in THF (0.3 mL) was treated with the product from Example 85A (0.019 g,0.047 mmol), DEPBT (0.013 g, 0.043 mmol), and N,N-diisopropylethylamine(0.07 mL, 0.402 mmol) and the mixture was stirred at 25° C. for 16hours. The mixture was partitioned between ethyl acetate and 10% Na₂CO₃solution. The organic phase was washed with additional 10% Na₂CO₃solution and brine, dried over MgSO₄, filtered and concentrated. Theresidue was purified by reversed phase chromatography on a C18 columneluting with 5-100% acetonitrile in water (0.1% TFA). The product waspartitioned between ethyl acetate and saturated NaHCO₃ solution. Theorganic phase was washed brine, dried over MgSO₄, filtered andconcentrated to give the title compound (0.010 g, 44% yield). ¹H NMR(300 MHz, DMSO-d₆), δ ppm 0.83 (s, 9 H), 0.90 (s, 9 H),1.27 (m, 1H),1.55 (m, 2 H), 2.41 (m, 1 H), 2.83 (m, 5 H), 3.24 (m, 1 H), 3.50 (s,3 H), 3.67 (m, 1 H), 3.85 (d, J=9.93 Hz, 1 H), 4.18 (m, 5 H), 4.56 (d,J=7.35 Hz, 1 H), 6.65 (d, J=9.93 Hz, 1 H), 7.11 (m, 5 H), 7.28 (m, 5 H),7.54 (d, J=9.19 Hz, 1 H), 7.87 (m, 5 H), 8.56 (d, J=5.88 Hz, 2 H), 8.64(d, J=4.41 Hz, 1 H).

EXAMPLE 86methyl(1S)-1-[({(1S,3S,4S)-4-({(2S)-3,3-dimethyl-2-[2-oxo-3-(2-pyridinylmethyl)-1-imidazolidinyl]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 86A(2S)-3,3-dimethyl-2-[2-oxo-3-(2-pyridinylmethyl)-1-imidazolidinyl]butanoicacid

A solution containing the product from Example 6F (0.10 g, 0.43 mmol) ina mixture of benzene (1.6 mL) and methanol (1.66 mL) was treated withpyridine-2-carboxaldehyde (0.041 mL, 0.43 mmol), stirred at 50° C. for18 hours, cooled to 25° C., treated with sodium borohydride (0.033 g,0.87 mmol), stirred at 25° C. for 1 hour, quenched with saturatedNaHCO₃, stirred for 1 hour, and partitioned between ethyl acetate andsaturated NaHCO₃. The organic phase was washed with brine and dried overMgSO₄, filtered and concentrated. A solution of the concentrate (0.43mmol) in 1,2-dichloroethane (7 mL) was treated with N,N-disuccinimidylcarbonate (0.134 g, 0.52 mmol) and triethylamine (0.07 mL, 0.50 mmol),stirred at 25° C. for 16 hours, diluted with chloroform and partitionedwith 10% Na₂CO₃. The organic phase was washed with brine, dried overMgSO₄, filtered and concentrated. A solution of the concentrate (0.43mmol) in dichloromethane (2 mL) was treated with trifluoracetic acid (2mL), stirred at 25° C. for 2 hours, concentrated, and azeotroped severaltimes with toluene to give the title compound (0.201 g), as thetrifluoroacetic acid salt.

EXAMPLE 86Bmethyl(1S)-1-[({(1S,3S,4S)-4-({(2S)-3,3-dimethyl-2-[2-oxo-3-(2-pyridinylmethyl)-1-imidazolidinyl]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 2C (0.015 g, 0.028 mmol)in THF (0.3 mL) was treated with the product from Example 85A (0.019 g,0.047 mmol), DEPBT (0.013 g, 0.043 mmol), and N,N-diisopropylethylamine(0.025 mL, 0.144 mmol) and the mixture was stirred at 25° C. for 16hours. The mixture was partitioned between ethyl acetate and 10% Na₂CO₃solution. The organic phase was washed with additional 10% Na₂CO₃solution and brine, dried over MgSO₄, filtered and concentrated. Theresidue was purified by reversed phase chromatography on a C18 columneluting with 5-100% acetonitrile in water (0.1% TFA). The product waspartitioned between ethyl acetate and saturated NaHCO₃ solution. Theorganic phase was washed brine, dried over MgSO₄, filtered andconcentrated to give the title compound (0.011 g, 48% yield). ¹H NMR(300 MHz, DMSO-d₆) δ ppm 0.83(s, 9H), 0.90(s, 9H), 1.60-1.51(m, 2H),2.44-2.35(q, J=9.07 Hz, 1H), 2.61-2.54(m, 1H), 2.69-2.66(d, J=6.99 Hz,2H), 2.81-2.76(m, 1H), 3.01-2.94(m, 1H), 3.14-3.05(m, 1H), 3.26-3.19(m,1H), 3.50(s, 3H), 3.70-3.62(m, 1H), 3.86-3.83(d, J=9.56 Hz, 1H), 4.08(s,1H), 4.25-4.11(m, 2H), 4.47-4.34(m, 2H), 4.57-4.54(d, J=7.72 Hz, 1H),6.65-6.63(d, J=9.17 Hz, 1H), 7.10-7.06(m, 5H), 7.26-7.21(m, 3H),7.32-7.28(m, 2H), 7.51-7.48(d, J=9.56 Hz, 1H), 7.91-7.79(m, 6H),8.55-8.54(d, J=3.68 Hz, 1H), 8.64-8.63(d, J=4.41 Hz, 1H).

EXAMPLE 87methyl(1S,4S,5S,7S,10S)-7-benzyl-1,10-ditert-butyl-5-hydroxy-4-[4-(6-methyl-3-pyridinyl)benzyl]-2,9,12-trioxo-13-oxa-3,8,11-triazatetradec-1-ylcarbamateEXAMPLE 87A 2-methyl-5-(tributylstannyl)pyridine

A solution containing 5-bromo-2-methylpyridine (1.2 g, 6.98 mmol) inether (14 mL) at −78° C. was treated with n-butyllithium (5.2 mL, 1.6 Min hexanes) dropwise, stirred at −78° C. for 1 hour, treated withtributyltin chloride (2.25 mL, 8.30 mmol), stirred at −78° C. for 0.5hours, and then at 0° C. for 0.5 hours. The reaction was quenched withsaturated ammonium chloride solution and the reaction was partitionedbetween ether and water, and the organic phase was washed with brine anddried over MgSO₄, filtered and concentrated to give the title compound(2.97 g), which was used without further purification.

EXAMPLE 87Bbenzyl(4S,5S)-5-{(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}-2,2-dimethyl-4-[4-(6-methyl-3-pyridinyl)benzyl]-1,3-oxazolidine-3-carboxylate

A solution containing the product from Example 23I (0.25 g, 0.354 mmol)in DMF (3.5 mL) was treated with LiCl (0.15 g, 3.54 mmol),dichlorobis(triphenylphosphine)palladium(II) (0.075 g, 0.107 mmol), andthe product from Example 87A (0.40 mL, 1.67 mmol), heated at 100° C. for16 hours, cooled and partitioned between ethyl acetate and water. Theorganic phase was washed with brine and dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with0-25% ethyl acetate in dichloromethane to give the title compound (0.193g, 84% yield).

EXAMPLE 87Cbenzyl(1S,2S,4S)-4-amino-2-hydroxy-1-[4-(6-methyl-3-pyridinyl)benzyl]-5-phenylpentylcarbamate

A solution containing the product from Example 87B (0.193 g, 0.297 mmol)in a mixture of THF (2 mL), methanol (2 mL), and aqueous HCl (2 mL, 1 N)was stirred at 60° C. for 16 hours. The solvent was removed underreduced pressure to give the title compound as the hydrochloride salt,which was used without further purification.

EXAMPLE 87D(2S,3S,5S)-2,5-diamino-1-[4-(6-methyl-3-pyridinyl)phenyl]-6-phenyl-3-hexanol

A solution containing the product from Example 87C (0.086 g, 0.148 mmol)in methanol (1.5 mL) was treated with Pd(OH)₂ on carbon (0.020 g, 20% Pdby wt.) and HCl solution (0.11 mL, 4N in dioxane), stirred under ahydrogen atmosphere (balloon pressure) at 25° C. for 16 hours, filteredthrough a bed of celite® and rinsed with methanol. The solvent wasconcentrated to give the title compound as the hydrochloride salt, whichwas used without further purification.

EXAMPLE 87Emethyl(1S,4S,5S,7S,10S)-7-benzyl-1,10-ditert-butyl-5-hydroxy-4-[4-(6-methyl-3-pyridinyl)benzyl]-2,9,12-trioxo-13-oxa-3,8,11-triazatetradec-1-ylcarbamate

A solution containing the product from Example 87D (0.148 mmol) in THF(1.5 mL) was treated with the product from Example 1F (0.070 g, 0.370mmol), DEPBT (0.14 g, 0.468 mmol), and N,N-diisopropylethylamine (0.26mL, 1.49 mmol) and the mixture was stirred at 25° C. for 16 hours. Themixture was partitioned between ethyl acetate and 10% Na₂CO₃ solution.The organic phase was washed with additional 10% Na₂CO₃ solution andbrine, dried over MgSO₄, filtered and concentrated. The product waspurified by chromatography on silica gel eluting with 0-100% ethylacetate/dichloromethane, followed by 0-5% methanol in ethyl acetate, togive the title compound (0.060 g, 56% yield). ¹H NMR (300 MHz, DMSO-d₆)δ ppm 0.77(s, 9H), 0.83(s, 9H), 1.56-1.54(m, 2H), 2.77-2.69(m, 3H),3.49(s, 3H), 3.54(s, 3H), 3.67-3.60(m, 1H), 3.81-3.78(d, J=9.93 Hz, 1H),3.95-3.92(d, J=9.56 Hz, 1H), 4.16-4.02(m, 2H), 4.86-4.84(d, J=5.88 Hz,1H), 6.64-6.61(d, J=9.93 Hz, 1H), 6.81-6.78(d, J=9.93 Hz, 1H),7.15-7.07(m, 5H), 7.33-7.28(m, 3H), 7.52-7.49(d, J=8.09 Hz, 2H),7.60-7.58(d, J=8.82 Hz, 1H), 7.76-7.73(d, J=8.09 Hz, 1H), 7.91-7.88(dd,J=8.09, 2.57 Hz, 1H), 8.70-8.69 (d, J=2.21 Hz, 1H).

EXAMPLE 88methyl(1S)-1-[({(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-1-[4-(6-methyl-3-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 88Abenzyl(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-1-[4-(6-methyl-3-pyridinyl)benzyl]-5-phenylpentylcarbamate

A solution containing the product from Example 87C (0.086 g, 0.148 mmol)in THF (1.5 mL) was treated with the product from Example 10D (0.060 g,0.176 mmol), DEPBT (0.067 g, 0.224 mmol), and N,N-diisopropylethylamine(0.26 mL, 1.49 mmol), stirred at 25° C. for 16 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was purified by chromatography onsilica gel eluting with 0-100% ethyl acetate/dichloromethane, followedby 0-5% methanol in ethyl acetate, to give the title compound (0.079 g,67% yield).

EXAMPLE 88B(2S)-N-{(1S,3S,4S)-4-amino-1-benzyl-3-hydroxy-5-[4-(6-methyl-3-pyridinyl)phenyl]pentyl}-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanamide

A solution containing the product from Example 88A (0.079 g, 0.099 mmol)in methanol (1.5 mL) was treated with Pd(OH)₂ on carbon (0.040 g, 20% Pdby wt.) and HCl solution (0.075 mL, 4N in dioxane), stirred under ahydrogen atmosphere (balloon pressure) at 25° C. for 16 hours, filteredthrough a bed of celite® and rinsed with methanol. The solvent wasconcentrated to give the title compound as the hydrochloride salt, whichwas used without further purification.

EXAMPLE 88Cmethyl(1S)-1-[({(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-1-[4-(6-methyl-3-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 88B (0.099 mmol) in THF(1 mL) was treated with the product from Example 1F (0.022 g, 0.116mmol), DEPBT (0.045 g, 0.151 mmol), and N,N-diisopropylethylamine (0.175mL, 1.00 mmol), stirred at 25° C. for 16 hours, and partitioned betweenethyl acetate and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was purified by chromatography on silica geleluting with 0-100% ethyl acetate/dichloromethane, followed by 0-5%methanol in ethyl acetate, to give the title compound (0.064 g, 77%yield). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.83(s, 9H), 0.86(s, 9H),1.59-1.49(m, 2H), 2.46-2.34(m, 2H), 2.46(s, 3H), 2.49(s, 3H),2.67-2.64(m, 1H), 2.77-2.75(d, J=6.99 Hz, 2H), 2.99-2.91(m, 1H),3.12-3.03(m, 1H), 3.26-3.17(m, 1H), 3.50(s, 3H), 3.66-3.58(m, 1H),3.96-3.93(m, 2H), 4.25-4.13(m, 2H), 4.40-4.28(m, 2H), 4.84-4.82(d,J=5.52 Hz, 1H), 6.84-6.81(d, J=9.56 Hz, 1H), 705-7.01(m, 6H),7.16-7.14(d, J=7.72 Hz, 1H), 7.33-7.29(dd, J=8.09, 4.04 Hz, 3H),7.51-7.49(d, J=8.09 Hz, 2H), 7.59-7.56(d, J=8.45 Hz, 1H), 7.71-7.65(t,J=7.72 Hz, 1H), 7.91-7.88(m, 2H), 8.69(d, J=2.21 Hz, 1H).

EXAMPLE 89methyl(1S)-1-[({(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(2-methyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-1-[4-(5-methyl-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 89Atert-butyl(1S,3S,4S)-4-amino-1-benzyl-3-hydroxy-5-[4-(5-methyl-2-pyridinyl)phenyl]pentylcarbamate

A solution containing the product from Example 74B (0.312 g, 0.48 mmol)in methanol (5 mL) was treated with Pd(OH)₂ on carbon (0.10 g, 20% Pd bywt.) and HCl solution (0.240 mL, 4N in dioxane), stirred under ahydrogen atmosphere (balloon pressure) at 25° C. for 16 hours, filteredthrough a bed of celite®, rinsed with methanol and concentrated. Theresidue was purified by reversed phase chromatography on a C18 columneluting with 5-100% acetonitrile in water (0.1% TFA) to give the titlecompound as the hydrochloride salt (0.178 g, 53% yield).

EXAMPLE 89Btert-butyl(1S,3S,4S)-1-benzyl-3-hydroxy-4-({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-5-[4-(5-methyl-2-pyridinyl)phenyl]pentylcarbamate

A solution containing the product from Example 89A (0.178 g, 0.302 mmol)in THF (4 mL) was treated with the product from Example 1F (0.074 g,0.393 mmol), DEPBT (0.136 g, 0.454 mmol), and N,N-diisopropylethylamine(0.527 mL, 3.02 mmol), stirred at 25° C. for 16 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated to give the title compound, which was usedwithout further purification.

EXAMPLE 89Cmethyl(1S)-1-[({(1S,2S,4S)-4-amino-2-hydroxy-1-[4-(5-methyl-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 89B (0.302 mmol) indichloromethane (2.5 mL) was treated with trifluoroacetic acid (2.5 mL),stirred at 25° C. for 16 hours and concentrated. The residue waspurified by reversed phase chromatography on a C18 column eluting with5-100% acetonitrile in water (0.1% TFA). The product was partitionedbetween ether and dilute ammonium hydroxide, and the organic phase wasdried over MgSO₄ filtered and concentrated to give the title compound(0.068 g, 42% yield).

EXAMPLE 89Dmethyl(1S)-1-[({(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(2-methyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-1-[4-(5-methyl-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 89C (0.040 g, 0.073 mmol)in THF (0.7 mL) was treated with the product from Example 14B (0.030 g,0.095 mmol), DEPBT (0.033 g, 0.110 mmol), and N,N-diisopropylethylamine(0.064 mL, 0.365 mmol) and the mixture was stirred at 25° C. for 16hours. The mixture was partitioned between ethyl acetate and 10% Na₂CO₃solution. The organic phase was washed with additional 10% Na₂CO₃solution and brine, dried over MgSO₄, filtered and concentrated. Theresidue was purified by chromatography on silica gel eluting with 0-100%ethyl acetate/dichloromethane, followed by 0-5% methanol in ethylacetate, to give the title compound (0.037 g, 60% yield). ¹H NMR (300MHz, DMSO-d₆) δ ppm 0.81(s, 9H), 0.86(s, 9H), 1.57-1.45(m, 2H), 2.32(s,3H), 2.45-2.37(m, 2H), 2.64(s, 3H), 2.69-2.58(m, 1H), 2.77-2.75(m, 2H),3.09-2.92(m, 2H), 3.26-3.17(m, 1H), 3.52(s, 3H), 3.66-3.54(m, 1H),3.97-3.94(m, 2H), 4.23-4.07(m, 2H), 4.42-4.23(m, 2H), 4.82(bs, 1H),6.58-6.54(J=8.09 Hz, 1H), 6.82-6.79(d, J=9.56 Hz, 1H), 7.08-6.95(m, 5H),7.21(s, 1H), 7.29-7.27(d, J=8.09 Hz, 2H), 7.60-7.57(d, J=8.82 Hz, 1H),7.68-7.64(dd, J=8.09, 2.21 Hz, 1H), 7.79-7.77(d, J=8.09 Hz, 1H),7.89-7.86(d, J=8.46 Hz, 2H), 8.47-8.46(d, J=2.21 Hz, 1H),

EXAMPLE 90methyl(1S,4S,5S,7S,10S)-7-benzyl-1,10-ditert-butyl-5-hydroxy-4-[4-(5-methyl-2-pyridinyl)benzyl]-2,9,12-trioxo-13-oxa-3,8,11-triazatetradec-1-ylcarbamate

A solution containing the product from Example 89C (0.032 g, 0.059 mmol)in THF (0.5 mL) was treated with the product from Example 1F (0.014 g,0.076 mmol), DEPBT (0.034 g, 0.114 mmol), and N,N-diisopropylethylamine(0.066 mL, 0.38 mmol) and the mixture was stirred at 25° C. for 16hours. The mixture was partitioned between ethyl acetate and 10% Na₂CO₃solution. The organic phase was washed with additional 10% Na₂CO₃solution and brine, dried over MgSO₄, filtered and concentrated. Theresidue was purified by chromatography on silica gel eluting with 0-100%ethyl acetate/dichloromethane, followed by 0-5% methanol in ethylacetate, to give the title compound (0.028 g, 61% yield). ¹H NMR (300MHz, DMSO-d₆) δ ppm 0.77 (s, 9H), 0.83(s, 9H), 1.58-1.39(m, 2H), 2.32(s,3H), 2.77-2.69(m, 3H), 3.51(s, 3H), 3.54(s, 3H), 3.67-3.60(m, 1H),3.81-3.78(d, J=9.93 Hz, 1H), 3.95-3.92(d, J=9.93 Hz, 1H), 4.17-4.01(m,2H), 4.86-4.84(d, J=5.52 Hz, 1H), 6.63-6.60(d, J=9.56 Hz, 1H),6.78-6.75(d, J=9.93 Hz, 1H), 7.14-7.06(m, 5H), 7.29-7.26(d, J=8.46 Hz,2H), 7.61-7.58(d, J=9.19 Hz, 1H), 7.68-7.65(m, 1H), 7.80-7.73(m, 2H),7.90-7.87(d, J=8.09 Hz, 2H), 8.47(s, 1H).

EXAMPLE 91methyl(1S)-1-[({(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2-methylbutylcarbamateEXAMPLE 91Atert-butyl(1S,2S,4S)-1-benzyl-2-hydroxy-4-({(2S,3S)-2-[(methoxycarbonyl)amino]-3-methylpentanoyl}amino)-5-[4-(2-pyridinyl)phenyl]pentylcarbamate

A solution containing the product from Example 2A (0.030 g, 0.060 mmol )in THF (0.6 mL) was treated with the product from Example 5A (0.014 g,0.074 mmol), DEPBT (0.030 g, 0.100 mmol), and N,N-diisopropylethylamine(0.050 mL, 0.287 mmol) and the mixture was stirred at 25° C. for 4hours. The mixture was partitioned between ethyl acetate and 10% Na₂CO₃solution. The organic phase was washed with additional 10% Na₂CO₃solution and brine, dried over MgSO₄, filtered and concentrated. Theresidue was chromatographed on silica gel eluting with 33-100% ethylacetate in chloroform to give the title compound (0.025 g, 66% yield).

EXAMPLE 91Bmethyl(1S,2S)-1-[({(1S,3S,4S)-4-amino-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2-methylbutylcarbamate

A solution containing the product from Example 2B (0.025 g, 0.040 mmol)in dichloromethane (1 mL) was treated with trifluoroacetic acid (1 mL)and the mixture was stirred at 25° C. for 1 hour. The solvent wasconcentrated and the mixture was partitioned between ethyl acetate andsaturated NaHCO₃ solution. The organic phase was washed with brine,dried over MgSO₄, filtered and concentrated.

EXAMPLE 91Cmethyl(1S)-1-[({(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2-methylbutylcarbamate

A solution containing the product from Example 91B (0.040 mmol) in THF(0.4 mL) was treated with the product from Example 10D (0.016 g, 0.047mmol), DEPBT (0.018 g, 0.060 mmol), and N,N-diisopropylethylamine (0.035mL, 0.201 mmol) and the mixture was stirred at 25° C. for 16 hours. Themixture was partitioned between ethyl acetate and 10% NaCO₃ solution.The organic phase was washed with additional 10% Na₂CO₃ solution andbrine, dried over MgSO₄, filtered and concentrated. The residue waschromatographed on silica gel eluting with 50% ethyl acetate inchloroform, followed by 5% methanol in chloroform to give the titlecompound (0.007 g, 22% yield). ¹H NMR (300 MHz, DMSO-d₆) δ ppm0.77-0.69(m, 6H), 0.90(s, 9H), 1.06-0.80(m, 2H), 1.40-1.22(m, 1H),1.67-1.48(m, 2H), 2.40-2.33(m, 1H), 2.46(s, 3H), 2.68-2.57(m, 3H),2.82-2.70(m, 1H), 3.01-2.92(m, 1H), 3.13-3.04(m, 1H), 3.27-3.17(m, 1H),3.52(s, 3H), 3.68-3.74(m, 1H), 3.80-3.74(m, 1H), 4.08(s, 1H),4.25-4.11(m, 2H), 4.41-4.29(m, 2H), 4.53-4.51(d, J=7.72 Hz, 1H),6.94-6.91(d, J=9.19 Hz, 1H), 7.17-7.03(m, 6H), 7.25-7.23(d, J=8.09 Hz,2H), 7.33-7.29(m, 1H), 7.51-7.48(d, J=9.56 Hz, 1H), 7.71-7.66(t, J=7.72Hz, 1H), 7.79-7.75(d, J=9.19 Hz, 1H), 7.947.85(m, 4H), 8.64-8.63(m, 1H).

EXAMPLE 92methyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-ditert-butyl-5-hydroxy-7-[4-(5-pyridinyl)benzyl]-2,9,12-trioxo-13-oxa-3,8,11-triazatetradec-1-ylcarbamateEXAMPLE 92Aethyl(5S)-3-(4-bromobenzyl)-5-{(1S)-1-[(tert-butoxycarbonyl)amino]-2-phenylethyl}-2-oxotetrahydro-3-furancarboxylate

A solution of tert-Butyl(1S)-1-[(2R)-oxiran-2-yl]-2-phenylethylcarbamate(10.0 g, 38.0 mmol) and diethyl malonate (5.8 ml, 38.2 mmol) in ethanol(30 mL) at 0° C. was treated with a solution of NaOEt (13.5 mL, 21% inethanol) over 10 minutes. The reaction was warmed to 25° C. and stirredfor 18 hours. The reaction was re-cooled to 0° C. and treated with asolution of 4-bromobenzyl bromide (9.5 g, 38.0 mmol) in ethanol (40 mL),stirred at 50° C. for 3 hours, cooled to 0° C. and adjusted to neutralpH by addition of 4N HCl. The ethanol was removed under reduced pressureand the residue was partitioned between chloroform and water. Theorganic phase was washed with brine and dried over MgSO₄, filtered andconcentrated to give the title compound (22.4 g), which was used withoutfurther purification.

EXAMPLE 92Btert-butyl(1S)-1-[(2S)-4-(4-bromobenzyl)-5-oxotetrahydro-2-furanyl]-2-phenylethylcarbamate

A solution of the product from Example 92A (22.4 g) in ethanol (120 mL)was treated with LiOH monohydrate (8.0 g, 190.7 mmol) solution in water(30 mL) and the mixture was stirred at 25° C. for 16 hours. The mixturewas cooled to 0° C., adjusted to pH 5 by addition of 4N HCl andpartitioned between dichloromethane and water. The organic phase waswashed with brine and dried over MgSO₄, filtered and concentrated. Asolution of the concentrate in toluene (400 mL) was then heated atreflux for 18 hours, cooled and concentrated to give the title compound(18.4 g), which was used without further purification.

EXAMPLE 92C(4S,5s)-2-(4-bromobenzyl)-5-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(dimethyl)silyl]oxy}-6-phenylhexanoicacid

A solution containing the product from Example 92B (18.4 g) in dioxane(190 mL) was treated with sodium hydroxide solution (45 mL, 1N) for 1hour at 25° C. The mixture was cooled to 0° C., and acidified to pH 5using 4N HCl, and concentrated under reduced pressure. The concentratewas partitioned between chloroform and water. The organic phase layerwas washed with brine, dried over MgSO₄, and concentrated. A solution ofthe residue (22 g) in dioxane (115 mL) was treated with imidazole (19 g,279 mmol) and t-butyldimethylsilyl chloride (35 g, 232 mmol), stirred at25° C. for 18 hours and concentrated. The residue was combined with ice,acidified with 4N HCl to pH 3, and extracted with ethyl acetate. Theorganic phase was washed with brine, dried over MgSO₄, filtered, andconcentrated. A solution of the residue in a mixture of THF (180 mL),acetic acid (180 mL), and water (60 mL) was stirred for 1 hour at 25° C.and concentrated. The residue was chromatographed on silica gel elutingwith 0-50% ethyl acetate in chloroform to give the title compound (14.18g, 60% yield).

EXAMPLE 92Dtert-butyl(1S,2S,4S)-1-benzyl-4-{[benzyloxycarbonyl]amino}-5-(4-bromophenyl)-2-{[tert-butyl(dimethyl)silyl]oxy}pentylcarbamate

A solution of the product from Example 92C (14.1 g, 23.3 mmol) intoluene (230 mL) was treated with DPPA (10.0 mL, 46.4 mmol) andtriethylamine (6.5 mL, 46.6 mmol), heated at reflux for 2 hours, treatedwith benzyl alcohol (7.2 mL, 69.9 mmol), heated at reflux for anadditional 16 hours, cooled and concentrated. The residue was purifiedby chromatography on silica gel, eluting with 20% ethyl acetate inhexanes to give the higher Rf product (2.94 g, 18% yield).

EXAMPLE 92Etert-butyl(1S,2S,4R)-1-benzyl-4-{[(benzyloxy)carbonyl]amino}-5-(4-bromophenyl)-2-{[tert-butyl(dimethyl)silyl]oxy}pentylcarbamate

A solution of the product from Example 92C (14.1 g, 23.3 mmol) intoluene (230 mL) was treated with diphenylphosphosphoryl azide (10.0 mL,46.4 mmol) and triethylamine (6.5 mL, 46.6 mmol), heated at reflux for 2hours, treated with benzyl alcohol (7.2 mL, 69.9 mmol), heated at refluxfor an additional 16 hours, cooled and concentrated. The residue waspurified by chromatography on silica gel, eluting with 20% ethyl acetatein hexanes to give the lower Rf product (3.21 g, 19% yield).

EXAMPLE 92Ftert-butyl(1S,2S,4S)-1-benzyl-4-{[(benzyloxy)carbonyl]amino}-2-{[tert-butyl(dimethyl)silyl]oxy}-5-[4-(5-methyl-2-pyridinyl)phenyl]pentylcarbamate

A solution containing the product from Example 92D (0.50 g, 0.703 mmol)in DMF (7 mL) was treated with LiCl (0.30 g, 7.08 mmol),dichlorobis(triphenylphosphine)palladium(II) (0.15 g, 0.213 mmol), andthe product from Example 74A (0.805 g, 2.11 mmol), heated at 100° C. for16 hours, cooled, filtered through celite®, and partitioned betweenethyl acetate and water. The organic phase was washed with brine anddried over MgSO₄, filtered and concentrated. The residue waschromatographed on silica gel eluting with 0-20% ethyl acetate inchloroform to give the title compound (0.374 g, 74% yield).

EXAMPLE 92Gtert-butyl(1S,2S,4S)-1-benzyl-4-{[(benzyloxy)carbonyl]amino}-2-hydroxy-5-[4-(5-methyl-2-pyridinyl)phenyl]pentylcarbamate

The product from Example 92F (0.374 g, 0.517 mmol) was treated with TBAFsolution in THF (2 mL, 1N), stirred at 25° C. for 16 hours, concentratedand partitioned between ethyl acetate and water. The organic phase waswashed with brined, dried over MgSO₄, filtered and concentrated. Theresidue was chromatographed on silica gel eluting with 0-20% ethylacetate in chloroform, to give the title compound (0.198 g, 63% yield).

EXAMPLE 92Htert-butyl(1S,2S,4S)-4-amino-1-benzyl-2-hydroxy-5-[4-(5-methyl-2-pyridinyl)phenyl]pentylcarbamate

A solution containing the product from Example 92G (0.198 g, 0.325 mmol)in a mixture of methanol (1.6 mL) and ethyl acetate (1.6 mL) was treatedwith Pd(OH)₂ on carbon (0.060 g, 20% Pd by wt.) and HCl solution (0.080mL, 4N in dioxane), stirred under a hydrogen atmosphere (balloonpressure) at 25° C. for 18 hours, filtered through a bed of celite® andrinsed with methanol. The solvent was concentrated to give the titlecompound as the hydrochloride salt, which was used without furtherpurification.

EXAMPLE 92Itert-butyl(1S,2S,4S)-1-benzyl-2-hydroxy-4-({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-5-[4-(5-methyl-2-pyridinyl)phenyl]pentylcarbamate

A solution containing the product from Example 92H (0.325 mmol) in THF(3.3 mL) was treated with the product from Example 1F (0.068 g, 0.360mmol), DEPBT (0.146 g, 0.488 mmol), and N,N-diisopropylethylamine (0.28mL, 1.61 mmol), stirred at 25° C. for 2 hours, and partitioned betweenethyl acetate and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with0-80% ethyl acetate in chloroform to give the title compound (0.120 g,56% yield).

EXAMPLE 92Jmethyl(1S)-1-[({(1S,3S,4S)-4-amino-3-hydroxy-1-[4-(5-methyl-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 92I (0.120 g, 0.183 mmol)in dichloromethane (1 mL) was treated with trifluoroacetic acid (1 mL),stirred at 25° C. for 1 hour. The solvent was concentrated and themixture was partitioned between chloroform and saturated NaHCO₃solution. The organic phase was washed with brine, dried over MgSO₄,filtered and concentrated, and the crude product (0.098 g) was usedwithout further purification.

EXAMPLE 92Kmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-ditert-butyl-5-hydroxy-7-[4-(5-methyl-2-pyridinyl)benzyl]-2,9,12-trioxo-13-oxa-3,8,11-triazatetradec-1-ylcarbamate

A solution containing the product from Example 92J (0.049 g, 0.090 mmol)in THF (1 mL) was treated with the product from Example 1F (0.018 g,0.095 mmol), DEPBT (0.040 g, 0.133 mmol), and N,N-diisopropylethylamine(0.080 mL, 0.459 mmol), stirred at 25° C. for 3 days, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The reaction was purified by reversed phasechromatography on a C18 column eluting with 5-100% acetonitrile in water(0.1% TFA). The product was partitioned between ethyl acetate and 10%Na₂CO₃, and the organic phase was washed with brine and dried overMgSO₄, filtered and concentrated to give the title compound (0.047 g,73% yield). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.79(s, 9H), 0.82(s, 9H),1.58-1.43(m, 2H), 2.32(s, 3H), 2.79-2.68(m, 3H), 3.49(s, 3H), 3.55(s,3H), 3.67-3.59(m, 1H), 3.843.80(d, J=9.93 Hz, 1H), 3.92-3.89(d, J=9.93Hz, 1H), 4.19-4.01(m, 2H), 4.87-4.85(d, J=5.88 Hz, 1H), 6.63-6.60(d,J=9.19 Hz, 1H), 6.81-6.77(d, J=9.56 Hz, 1H), 7.19-7.12(m, 5H),7.56-7.53(d, J=8.82 Hz, 1H), 7.68-7.64(m, 1H), 7.81-7.76(m, 3H),7.86-7.83(d, J=8.09 Hz, 2H), 8.47(bs, 1H).

EXAMPLE 93methyl(1S)-1-[({(1S,3S,4S)-4-{[(2S)-2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-3-hydroxy-1-[4-(5-methyl-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 92J (0.050 g, 0.092 mmol)in THF (1 mL) was treated with the product from Example 70A (0.028 g,0.097 mmol), DEPBT (0.041 g, 0.137 mmol), and N,N-diisopropylethylamine(0.080 mL, 0.459 mmol), stirred at 25° C. for 16 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was purified by reversed phasechromatography on a C18 column eluting with 5-100% acetonitrile in water(0.1% TFA). The product was partitioned between ethyl acetate andsaturated NaHCO₃, and the organic phase was washed with brine and driedover MgSO₄, filtered and concentrated to give the title compound (0.036g, 48% yield). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.83(s, 9H), 0.89(s, 9H),1.60-1.49(m, 2H), 2.32(s, 3H), 2.60-2.53(m, 1H), 2.68-2.65(d, J=6.99 Hz,2H), 2.88-2.75(m, 2H), 2.96-2.90(q, J=8.70 Hz, 1H), 3.24-3.15(m, 1H),3.51(s, 3H), 3.71-3.61(m, 1H), 3.87-3.83(d, J=9.56 Hz, 1H), 4.09(s, 1H),4.22-4.11 (m, 2H), 4.31(s, 2H), 4.56-4.53(d, J=7.72 Hz, 1H),6.67-6.63(d, J=9.56 Hz, 1H), 7.08-7.02(m, 5H), 7.21-7.19(d, J=8.46 Hz,2H), 7.31-7.26(m, 3H), 7.40-7.35(m, 2H), 7.50-7.46 (d, J=9.56 Hz, 1H),7.68-7.64(dd, J=8.27, 2.02 Hz, 1H), 7.82-7.77(m, 2H), 7.88-7.85(d,J=8.09 Hz, 2H), 8.47-8.46(d, J=2.21 Hz, 1H).

EXAMPLE 94methyl(1S)-1-[({(1S,2S,4R)-1-benzyl-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-[4-(2-pyridinyl)phenyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 94Atert-butyl(1S,2S,4R)-1-benzyl-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-[4-(2-pyridinyl)phenyl]pentylcarbamate

A solution containing the product from Example 1E (0.050 g, 0.101 mmol)in THF (1 mL) was treated with the product from Example 10D (0.034 g,0.100 mmol), DEPBT (0.045 g, 0.151 mmol), and N,N-diisopropylethylamine(0.090 mL, 0.517 mmol), stirred at 25° C. for 4 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was purified by reversed phasechromatography on a C18 column eluting with 5-100% acetonitrile in water(0.1% TFA). The product was partitioned between dichloromethane andsaturated NaHCO₃ solution. The organic phase was washed brine, driedover MgSO₄, filtered and concentrated. The residue was thenchromatographed on silica gel eluting with 0-10% methanol in chloroform,to give the title compound (0.042 g, 56% yield).

EXAMPLE 94Bmethyl(1S)-1-[({(1S,2S,4R)-1-benzyl-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-[4-(2-pyridinyl)phenyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 94A (0.042 g, 0.056 mmol)in dichloromethane (0.3 mL) was treated with trifluoroacetic acid (0.3mL) and the mixture was stirred at 25° C. for 1 hour. The solvent wasconcentrated and the residue was dissolved in toluene and concentratedseveral times. A solution of the residue (0.056 mmol) in THF (0.6 mL)was treated with the product from Example 1F (0.011 g, 0.058 mmol),DEPBT (0.025 g, 0.083 mmol), and N,N-diisopropylethylamine (0.049 mL,0.281 mmol), stirred at 25° C. for 2 hours, and partitioned betweenethyl acetate and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was purified by reversed phase chromatographyon a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA).The product was partitioned between ethyl acetate and saturated NaHCO₃,and the organic phase was washed with brine and dried over MgSO₄,filtered and concentrated to give the title compound (0.023 g, 48%yield). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.77(s, 9H), 0.81(s, 9H),1.41-1.31(m, 1H), 1.59-1.49(m, 1H), 2.43(s, 3H), 2.70-2.59(m, 3H),2.88-2.77(m, 1H), 3.25-3.12(m, 2H), 3.53(s, 3H), 3.64-3.44(m, 2H),3.94-3.84(m, 2H), 4.08(s, 1H), 4.19-4.10(m, 2H), 4.43-4.26(m, 2H),6.77-6.73(d, J=9.56 Hz, 1H), 7.03-7.01(d, J=7.72 Hz, 1H), 7.18-7.09(m,5H), 7.28-7.25(d, J=8.46 Hz, 2H), 7.34-7.30(m, 2H), 7.53-7.50(d, J=9.93Hz, 1H), 7.65-7.60(t, J=7.72 Hz, 1H), 7.92-7.83(m, 2H), 7.97-7.95(d,J=8.09 Hz, 2H), 8.17-8.15(d, J=8.46 Hz, 1H), 8.65-8.64(d, J=4.78 Hz,1H).

EXAMPLE 95 1:1 mixture ofmethyl(1R,4S,5S,7S,10S)-4-benzyl-10-tert-butyl-5-hydroxy-1-[1-methyl-1-(R)-methylsulfinyl)ethyl]-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamateandmethyl(1R,4S,5S,7S,10S)-4-benzyl-10-tert-butyl-5-hydroxy-1-[1-methyl-1-((S)-methylsulfinyl)ethyl]-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate

A solution containing the product from Example 30B (0.015 g, 0.020mmol)in a mixture of THF (0.15 mL), acetone (0.15 mL), and water (0.05mL) was treated with NMO (0.003 g, 0.026 mmol) and aqueous osmiumtetroxide solution (0.030 mL, 4%), was stirred for 16 hours at 25° C.,and partitioned between ethyl acetate and water. The organic phase waswashed with brine and dried over MgSO₄, filtered and concentrated. Theresidue was chromatographed on silica gel eluting with 0-100% ethylacetate/dichloromethane, followed by 0-10% methanol in dichloromethaneto give the title compound (0.006 g, 39% yield). ¹H NMR (300 MHz,DMSO-d₆), δ ppm 0.81 (s, 9 H), 1.02 (m, 7 H), 1.50 (m, 2 H), 2.29 (s, 1H), 2.38 (s, 2 H), 2.76 (m, 3 H), 3.50 (s, 3 H), 3.55 (s, 3 H), 3.68 (m,1 H), 3.83 (d, J=9.93 Hz, 1 H), 4.08 (m, 2 H), 4.33 (m, 1 H), 5.01 (d,J=5.15 Hz, 1 H), 6.63 (d, J=9.56 Hz, 1 H), 7.22 (m, 9 H), 7.86 (m, 6 H),8.63 (d, J=4.41 Hz, 1 H).

EXAMPLE 96methyl(1S)-1-[({(1S,2S,4S)-2-hydroxy-4-[((2S)-3-methyl-2-{3-[(1-methyl-1H-benzimidazol-2-yl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 96Atert-butyl(2S,3S)-2-[(2-{[(9H-fluoren-9-ylmethoxy)carbonyl][(1-methyl-1H-benzimidazol-2-yl)methyl]amino}ethyl)amino]-3-methylpentanoate

A solution of the product of Example 59C (0.81 mmol ) and (L)-methyliso-leucinate hydrochloride (0.182 g, 0.813 mmol) in methanol (3.2 mL)and acetic acid (0.032 mL) was treated with NaCNBH₃ (0.104 g, 1.65mmol), stirred at 25° C. for 1 hour, and partitioned between water anddichloromethane. The organic phase layer was separated and washed with1N NaHCO₃ and brine, dried over Na₂SO₄, filtered and concentrated. Thecrude product was used without further purification.

EXAMPLE 96Btert-butyl(2S,3S)-3-methyl-2-{3-[(1-methyl-1H-benzimidazol-2-yl)methyl]-2-oxo-1-imidazolidinyl}pentanoate

A solution of the product of Example 96A (0.81 mmol) inN,N-dimethylformamide (5 mL) was treated with diethylamine (0.8 mL),stirred at 25° C. for 2 hours and concentrated. A solution of theresidue in 1,2-dichloroethane (16 mL) was treated withbis-(p-nitrophenyl)carbonate (0.296 g, 0.973 mmol), stirred at 60° C.for 16 hours and concentrated. The residue was chromatographed on silicagel, eluting with 0-100% ethyl acetate/dichloromethane to give the titlecompound (0.192 g, 59% yield).

EXAMPLE 96C(2S,3S)-3-methyl-2-{3-[(1-methyl-1H-benzimidazol-2-yl)methyl]-2-oxo-1-imidazolidinyl}pentanoicacid

A solution containing the product from Example 96B (0.037 g, 0.093 mmol)in dichloromethane (0.45 mL) was treated with trifluoroacetic acid (0.45mL), stirred for 2 hours at 25° C. The solvent was concentrated and theresidue was dissolve in ethyl acetate and concentrated to give the titlecompound as the trifluoroacetic acid salt, which was used withoutpurification.

EXAMPLE 96Dmethyl(1S)-1-[({(1S,2S,4S)-2-hydroxy-4-[((2S)-3-methyl-2-{3-[(1-methyl-1H-benzimidazol-2-yl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 23S (0.020 g, 0.038 mmol)in THF (0.5 mL) was treated with the product from Example 96C (0.021 g,0.046 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine(0.035 mL, 0.201 mmol), stirred at 25° C. for 1 hour, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was chromatographed on silica geleluting with 0-100% ethyl acetate/dichloromethane, followed by 0-5%methanol in ethyl acetate, to give the title compound (0.022 g, 68%yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.60 (d, J=6.25 Hz, 3 H), 0.72(t, J=7.35 Hz, 3 H), 0.85 (m, 12 H), 1.24 (m, 1 H), 1.51 (m, 2 H), 1.73(m, 1 H), 2.67 (m, 1 H), 2.77 (d, J=6.62 Hz, 2 H), 2.89 (m, 1 H), 3.08(m, 2 H), 3.51 (s, 3 H), 3.59 (m, 1 H), 3.77 (s, 3 H), 3.85 (d, J=11.03Hz, 1 H), 3.94 (d, J=9.93 Hz, 1 H), 4.15 (m, 2 H), 4.59 (s, 2 H), 4.82(d, J=5.52 Hz, 1 H), 6.80 (d, J=10.30 Hz, 1 H), 6.99 (m, 5 H), 7.24 (m,5 H), 7.56 (m, 3 H), 7.88 (m, 5 H), 8.63 (d, J=4.41 Hz, 1 H).

EXAMPLE 97methyl(1S)-1-[({(1S,2S,4S)-2-hydroxy-4-[((2S)-2-{3-[(2-isopropyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}-3-methylpentanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 97A 2-isopropyl-1,3-thiazole-4-carbaldehyde

A solution containing the product from Example 56B (18 g, 90.5 mmol) indichloromethane (100 mL) was treated with DIBAL (150 mL, 1 M indichloromethane) dropwise at −78° C. over 2 hours, stirred at −78° C.for 2 hours, treated with acetic acid (10 mL), warmed to 25° C., treatedwith 10% solution of aqueous sodium potassium tartrate, stirredvigorously for 1 hour, and partitioned between dichloromethane andwater. The organic phase was washed with brine and dried over MgSO₄,filtered and concentrated. The residue was chromatographed on silica geleluting 0-5% ethyl acetate in dichloromethane to give the title compound(5.24 g, 40% yield).

EXAMPLE 97Btert-butyl(2S,3S)-2-{3-[(2-isopropyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}-3-methylpentanoate

A solution containing the product from Example 3G (1.304 g, 5.66 mmol)in a mixture of benzene (15 mL) and methanol (15 mL) was treated withthe product from Example 97A (1.05 g, 6.79 mmol), was heated at 50° C.for 3 hours, cooled to 0° C., treated with sodium borohydride (0.428 g,11.32 mmol), stirred at 25° C. for 16 hours, quenched with sodiumbicarbonate solution, and partitioned between ethyl acetate and water.The organic phase was washed with brine and dried over MgSO₄, filteredand concentrated. A solution of the concentrate (5.66 mmol) in toluene(30 mL) was treated with bis(4-nitrophenyl)carbonate (2.066 g, 6.79mmol), heated at 100° C. for 16 hours, cooled and partitioned betweenethyl acetate and saturated NaHCO₃. The organic phase was washed withbrine and dried over MgSO₄, filtered and concentrated. The residue waschromatographed on silica gel eluting with 0-25% ethyl acetate indichloromethane to give the title compound (1.68 g, 75% yield).

EXAMPLE 97C(2S,3S)-2-{3-[(2-isopropyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}-3-methylpentanoicacid

A solution containing the product from Example 97B (1.68 g, 4.25 mmol)in dichloromethane (14 mL) was treated with trifluoracetic acid (7 mL),was stirred at 25° C. for 2 hours, and concentrated to give the titlecompound as the trifluoroacetic acid salt, which was used withoutfurther purification.

EXAMPLE 97Dmethyl(1S)-1-[({(1S,2S,4S)-2-hydroxy-4-[((2S)-2-{3-[(2-isopropyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}-3-methylpentanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 23S (0.020 g, 0.038 mmol)in THF (0.5 mL) was treated with the product from Example 97C (0.020 g,0.044 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine(0.035 mL, 0.201 mmol), stirred at 25° C. for 1 hour, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was chromatographed on silica geleluting with 0-100% ethyl acetate/dichloromethane, followed by 0-5%methanol in ethyl acetate, to give the title compound (0.024 g, 75%yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.59 (d, J=6.25 Hz, 3 H), 0.72(t, J=7.17 Hz, 3 H), 0.86 (s, 10 H), 1.28 (m, 7 H), 1.52 (m, 2 H), 1.72(m, 1 H), 2.41 (m, 1 H), 6.25 (m, 1 H), 2.80 (m, 3 H), 3.07 (m, 4 H),3.51 (s, 3 H), 3.59 (m, 1 H), 3.83 (d, J=11.03 Hz, 1 H), 3.94 (d, J=9.56Hz, 1 H), 4.14 (m, 2 H), 4.33 (m, 2 H), 4.80 (d, J=5.52 Hz, 1 H), 6.79(d, J=9.19 Hz, 1 H), 7.04 (s, 5 H), 7.22 (s, 1 H), 7.31 (m, 3 H), 7.58(d, J=8.46 Hz, 1 H), 7.86 (m, 5 H), 8.63 (d, J=4.04 Hz, 1 H).

EXAMPLE 98methyl(1S)-1-[({(1R,3S,4S)-3-hydroxy-4-[((2S)-3-methyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}pentanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 1H (0.020 g, 0.038 mmol)in THF (0.4 mL) was treated with the product from Example 7B (0.020 g,0.048 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine(0.035 mL, 0.201 mmol), stirred at 25° C. for 1 hour, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was chromatographed on silica geleluting with 0-100% ethyl acetate/dichloromethane, followed by 0-5%methanol in ethyl acetate, to give the title compound (0.025 g, 81%yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.83 (m, 16 H), 1.29 (m, 2 H),1.55 (m, 1 H), 1.80 (m, 1 H), 2.44 (s, 3 H), 2.71 (m, 5 H), 3.09 (m, 3H), 3.54 (m, 4 H), 3.85 (m, 3 H), 4.18 (m, 1 H), 4.33 (s, 2 H), 4.56 (d,J=6.99 Hz, 1 H), 6.88 (d, J=9.56 Hz, 1 H), 7.01 (d, J=7.35 Hz, 1 H),7.12 (m, 6 H), 7.23 (d, J=8.09 Hz, 2 H), 7.32 (m, 2 H), 7.64 (t, J=7.72Hz, 1 H), 7.88 (m, 5 H), 8.64 (d, J=4.78 Hz, 1 H).

EXAMPLE 99methyl(1S)-1-[({(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(1-methyl-1H-benzimidazol-2-yl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 2C (0.025 g, 0.047 mmol)in THF (0.5 mL) was treated with the product from Example 59F (0.020 g,0.061 mmol), DEPBT (0.021 g, 0.071 mmol), and N,N-diisopropylethylamine(0.041 mL, 0.235 mmol), stirred at 25° C. for 2 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The reaction was purified by reversed phasechromatography on a C18 column eluting with 5-100% acetonitrile in water(0.1% TFA). The residue was partitioned between ethyl acetate andsaturated NaHCO₃, and the organic phase was washed with brine and driedover MgSO₄, filtered and concentrated to give the title compound (0.006g, 14% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.83 (s, 9 H), 0.89 (s,9 H), 1.26 (m, 1 H), 1.52 (m, 2 H), 2.32 (m, 1 H), 2.70 (m, 4 H), 2.98(m, 1 H), 3.09 (m, 2 H), 3.46 (s, 1 H), 3.50 (s, 3 H), 3.81 (s, 3 H),4.15 (m, 3 H), 4.53 (dd, J=11.40, 3.68 Hz, 2 H), 4.70 (d, J=15.44 Hz, 1H), 6.63 (d, J=9.56 Hz, 1 H), 6.93 (m, 3 H), 7.07 (d, J=6.62 Hz, 2 H),7.24 (m, 6 H), 7.59 (m, 3 H), 7.88 (m, 4 H), 8.63 (d, J=3.31 Hz, 1 H).

EXAMPLE 100methyl(1S)-1-[({(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(1-methyl-1H-benzimidazol-2-yl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 23S (0.011 g, 0.021 mmol)in THF (0.3 mL) was treated with the product from Example 59F (0.007 g,0.020 mmol), DEPBT (0.009 g, 0.030 mmol), and N,N-diisopropylethylamine(0.018 mL, 0.103 mmol), stirred at 25° C. for 3 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was purified by reversed phasechromatography on a C18 column eluting with 5-100% acetonitrile in water(0.1% TFA). The product was partitioned between ethyl acetate andsaturated NaHCO₃, and the organic phase was washed with brine and driedover MgSO₄, filtered and concentrated to give the title compound (0.009g, 51% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.82 (s, 9 H), 0.86 (s,9 H), 1.27 (m, 1 H), 1.53 (m, 2 H), 2.36 (m, 2 H), 2.72 (m, 3 H), 2.98(m, 1 H), 3.10 (m, 1 H), 3.48 (d, J=13.97 Hz, 3 H), 3.61 (m, 1 H), 3.80(s, 3 H), 3.93 (m, 2 H), 4.16 (m, 2 H), 4.60 (m, 2 H), 4.83 (d, J=5.52Hz, 1 H), 6.91 (m, 4 H), 7.02 (m, 2 H), 7.20 (m, 2 H), 7.29 (m, 3 H),7.58 (m, 3 H), 7.87 (m, 5 H), 8.63 (d, J=4.78 Hz, 1 H).

EXAMPLE 101methyl(1S)-1-[({(1S,3S,4S)-3-hydroxy-4-[((2S)-2-{3-[(2-isopropyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}-3,3-dimethylbutanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 101Atert-butyl(2S)-2-{3-[(2-isopropyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}-3,3-dimethylbutanoate

A solution containing the product from Example 6F (0.060 g, 0.253 mmol)in a mixture of benzene (0.7 mL) and methanol (0.7 mL) was treated withthe product from Example 97A (0.043 g, 0.278 mmol), heated at 50° C. for3 hours, cooled to 0° C., treated with sodium borohydride (0.019 g,0.506 mmol), stirred at 25° C. for 16 hours, quenched with sodiumbicarbonate solution and partitioned between ethyl acetate and water.The organic phase was washed with brine and dried over MgSO₄, filteredand concentrated. A solution of the concentrate (0.253 mmol) in toluene(1.5 mL) was treated with bis(4-nitrophenyl)carbonate (0.092 g, 0.304mmol), heated at 100° C. for 16 hours, cooled and partitioned betweenethyl acetate and saturated NaHCO₃. The organic phase was washed withbrine and dried over MgSO₄, filtered and concentrated. The residue waschromatographed on silica gel eluting with 0-25% ethyl acetate indichloromethane to give the title compound (0.075 g, 75% yield).

EXAMPLE 101B(2S)-2-{3-[(2-isopropyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}-3,3-dimethylbutanoicacid

A solution containing the product from Example 97B (0.075 g, 0.190 mmol)in dichloromethane (0.5 mL) was treated with trifluoracetic acid (0.5mL), was stirred at 25° C. for 2 hours, and concentrated to give thetitle compound as the trifluoroacetic acid salt, which was used withoutfurther purification.

EXAMPLE 101Cmethyl(1S)-1-[({(1S,3S,4S)-3-hydroxy-4-[((2S)-2-{3-[(2-isopropyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}-3,3-dimethylbutanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 2C (0.020 g, 0.038 mmol)in THF (0.5 mL) was treated with the product from Example 101B (0.015 g,0.045 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine(0.033 mL, 0.189 mmol), stirred at 25° C. for 2 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was chromatographed on silica geleluting with 0-100% ethyl acetate/dichloromethane, followed by 0-5%methanol in ethyl acetate, to give the title compound (0.019 g, 59%yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.83 (s, 9 H), 0.88 (s, 9 H),1.31 (m, 6 H), 1.53 (m, 2 H), 2.30 (m, 1 H), 2.62 (m, 3 H), 2.79 (m, 1H), 3.02 (m, 2 H), 3.22 (m, 2 H), 3.50 (s, 3 H), 3.66 (m, 1 H), 3.85 (d,J=9.56 Hz, 1 H), 4.20 (m, 4 H), 4.45 (m, 1 H), 4.53 (d, J=7.35 Hz, 1 H),6.63 (d, J=9.93 Hz, 1 H), 7.03 (m, 5 H), 7.28 (m, 4 H), 7.45 (d, J=9.56Hz, 1 H), 7.86 (m, 5 H), 8.64 (d, J=4.41 Hz, 1 H)

EXAMPLE 102methyl(1S)-1-[({(1S,2S,4S)-2-hydroxy-4-[((2S)-2-{3-[(2-isopropyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}-3,3-dimethylbutanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 23S (0.018 g, 0.033 mmol)in THF (0.5 mL) was treated with the product from Example 101B (0.014 g,0.041 mmol), DEPBT (0.015 g, 0.051 mmol), and N,N-diisopropylethylamine(0.030 mL, 0.171 mmol), stirred at 25° C. for 2 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was chromatographed on silica geleluting with 0-100% ethyl acetate/dichloromethane, followed by 0-5%methanol in ethyl acetate, to give the title compound (0.018 g, 62%yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.81 (s, 9 H), 0.86 (s, 9 H),1.32 (d, J=6.99 Hz, 6 H), 1.52 (m, 2 H), 2.38 (m, 2 H), 2.64 (d, J=9.93Hz, 1 H), 2.77 (d, J=6.99 Hz, 2 H), 3.01 (m, 2 H), 3.23 (m, 2 H), 3.51(s, 3 H), 3.61 (m, 1 H), 3.95 (m, 2 H), 4.30 (m, 4 H), 4.82 (d, J=5.52Hz, 1 H), 6.79 (d, J=9.19 Hz, 1 H), 7.00 (m, 5 H), 7.24 (s, 1 H), 7.30(m, 3 H), 7.58 (d, J=9.56 Hz, 1 H), 7.87 (m, 5 H), 8.63 (d, J=4.41 Hz, 1H).

EXAMPLE 103methyl(1S,4S,5S,7S,10S)-7-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-4-[4-(3-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamateEXAMPLE 103Abenzyl(1S,2S,4S)-4-amino-2-hydroxy-5-phenyl-1-[4-(3-pyridinyl)benzyl]pentylcarbamate

A solution containing the product from Example 67A (0.059 g, 0.093 mmol)in a mixture of methanol (3 mL) and aqueous HCl (1 mL, 1 N) was stirredat 50° C. for 2 hours, and concentrated to give the title compound asthe hydrochloride salt, which was used without further purification.

EXAMPLE 103B(2S,3S,5S)-2,5-diamino-6-phenyl-1-[4-(3-pyridinyl)phenyl]-3-hexanol

A solution containing the product from Example 103A (0.093 mmol) inmethanol (2 mL) was treated with Pd(OH)₂ on carbon (0.050 g, 20% Pd bywt.) and HCl solution (0.040 mL, 4N in dioxane), stirred under ahydrogen atmosphere (balloon pressure) at 25° C. for 2 hours, filteredthrough a bed of celite®, rinsed with methanol, and concentrated to givethe title compound as the hydrochloride salt, which was used withoutfurther purification.

EXAMPLE 103Cmethyl(1S,4S,5S,7S,10S)-7-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-4-[4-(3-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate

A solution containing the product from Example 103B (0.093 mmol) in THF(1 mL) was treated with the product from Example 1F (0.040 g, 0.211mmol), DEPBT (0.085 g, 0.284 mmol), and N,N-diisopropylethylamine (0.175mL, 1.00 mmol), stirred at 25° C. for 1 hour, and partitioned betweenethyl acetate and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was purified by chromatography on silica geleluting with 0-100% ethyl acetate/dichloromethane, followed by 0-5%methanol in ethyl acetate, to give the title compound (0.035 g, 55%yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.77 (s, 9 H), 0.83 (s, 9 H),1.50 (m, 2 H), 2.73 (m, 4 H), 3.48 (s, 3 H), 3.54 (s, 3 H), 3.64 (m, 1H), 3.80 (d, J=10.30 Hz, 1 H), 3.93 (d, J=9.19 Hz, 1 H), 4.12 (m, 2 H),4.84 (d, J=5.52 Hz, 1 H), 6.61 (d, J=9.56 Hz, 1 H), 6.78 (d, J=8.82 Hz,1 H), 7.11 (m, 5 H), 7.32 (d, J=8.09 Hz, 2 H), 7.47 (dd, J=7.72, 5.15Hz, 1 H), 7.56 (m, 3 H), 7.73 (d, J=8.46 Hz, 1 H), 8.01 (m, 1 H), 8.54(dd, J=4.60, 1.65 Hz, 1 H), 8.84 (d, J=1.84 Hz, 1 H).

EXAMPLE 104methyl(1S,4S,5S,7S,10S)-7-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-4-[4-(4-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamateEXAMPLE 104Abenzyl(1S,2S,4S)-2-hydroxy-4-({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-5-phenyl-1-[4-(4-pyridinyl)benzyl]pentylcarbamate

A solution containing the product from Example 73B (0.045 mmol) in THF(0.45 mL) was treated with the product from Example 1F (0.010 g, 0.053mmol), DEPBT (0.020 g, 0.067 mmol), and N,N-diisopropylethylamine (0.080mL, 0.459 mmol), stirred at 25° C. for 0.5 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated to give the title compound, which was usedwithout further purification.

EXAMPLE 104Bmethyl(1S)-1-[({(1S,3S,4S)-4-amino-1-benzyl-3-hydroxy-5-[4-(4-pyridinyl)phenyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 104A (0.045 mmol) inmethanol (0.5 mL) was treated with Pd(OH)₂ on carbon (0.010 g, 20% Pd bywt.) and HCl solution (0.035 mL, 4N in dioxane), stirred under ahydrogen atmosphere (balloon pressure) for 4 hours at 25° C., filteredthrough a bed of celite®, rinsed with methanol, and concentrated to givethe title compound as the hydrochloride salt, which was used withoutfurther purification.

EXAMPLE 104Cmethyl(1S,4S,5S,7S,10S)-7-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-4-[4-(4-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate

A solution containing the product from Example 104B (0.045 mmol) in THF(0.45 mL) was treated with the product from Example 1F (0.010 g, 0.053mmol), DEPBT (0.020 g 0.067 mmol), and N,N-diisopropylethylamine (0.080mL, 0.459 mmol), stirred at 25° C. for 1 hour, and partitioned betweenethyl acetate and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was purified by reversed phase chromatographyon a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA).The product was partitioned between ethyl acetate and saturated NaHCO₃,and the organic phase was washed with brine and dried over MgSO₄,filtered and concentrated to give the title compound (0.008 g, 25%yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.77 (s, 9 H), 0.82 (s, 9 H),1.48 (m, 2 H), 2.75 (m, 4 H), 3.49 (s, 3 H), 3.54 (s, 3 H), 3.63 (m, 1H), 3.80(d, J=9.93 Hz, 1 H), 3.93 (d, J=9.56 Hz, 1 H), 4.10 (m, 2 H),4.85 (d, J=5.52 Hz, 1 H), 6.60 (d, J=9.19 Hz, 1 H), 6.76 (d, J=10.30 Hz,1 H), 7.10 (m, 5 H), 7.33 (d, J=8.09 Hz, 2 H), 7.64 (m, 6 H), 8.61 (m, 2H).

EXAMPLE 105methyl(1S)-1-[({(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(2-methyl-1,3-thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 2C (0.044 g, 0.082 mmol)in THF (0.7 mL) was treated with the product from Example 14B (0.033 g,0.107 mmol), DEPBT (0.037 g, 0.124 mmol), and N,N-diisopropylethylamine(0.072 mL, 0.412 mmol), stirred at 25° C. for 2 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was purified by chromatography onsilica gel eluting with 0-100% ethyl acetate dichloromethane, followedby 0-5% methanol in ethyl acetate, to give the title compound (0.056 g,83% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.83 (s, 9 H), 0.88 (s, 9H), 1.54 (m, 2 H), 2.36 (q, J=9.31 Hz, 1 H), 2.61 (m, 5 H), 2.78 (m, 1H), 3.01 (m, 2 H), 3.22 (m, 2 H), 3.50 (s, 3 H), 3.66 (m, 1 H), 3.85 (d,J=9.56 Hz, 1 H), 4.17 (m, 4 H), 4.41 (m, 1 H), 4.54 (d, J=7.35 Hz, 1 H),6.63 (d, J=9.56 Hz, 1 H), 7.06 (m, 5 H), 7.21 (s, 1 H), 7.24 (s, 2 H),7.31 (m, 1 H), 7.45 (d, J=9.56 Hz, 1 H), 7.87 (m, 5 H), 8.63 (d, J=4.41Hz, 1 H).

EXAMPLE 106methyl(1S)-1-[({(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(2-methyl-1,3thiazol-4-yl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 23S (0.038 g, 0.071 mmol)in THF (0.7 mL) was treated with the product from Example 14B (0.029 g,0.092 mmol), DEPBT (0.032 g, 0.107 mmol), and N,N-diisopropylethylamine(0.062 mL, 0.355 mmol) stirred at 25° C. for 2 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was purified by chromatography onsilica gel eluting with 0-100% ethyl acetate/dichloromethane, followedby 0-5% methanol in ethyl acetate, to give the title compound (0.041 g,70% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.81 (s, 9 H), 0.86 (s, 9H), 1.53 (m, 2 H), 2.39 (m, 2 H), 2.64 (m, 4 H), 2.77 (d, J=6.62 Hz, 2H), 3.00 (m, 2 H), 3.19 (m, 1 H), 3.51 (s, 3 H), 3.61 (m, 1 H), 3.96 (m,2 H), 4.32 (m, 4 H), 4.82 (d, J=5.52 Hz, 1 H), 6.79 (d, J=9.56 Hz, 1 H),7.04 (m, 5 H), 7.21 (s, 1 H), 7.30 (m, 3 H), 7.58 (d, J=8.82 Hz, 1 H),7.87 (m, 5 H), 8.63 (d, J=4.78 Hz, 1 H).

EXAMPLE 107methyl(1S)-1-[({(1S,3R,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 107Aethyl(5R)-5-{(1S)-1-[(tert-butoxycarbonyl)amino]-2-phenylethyl}-2-oxotetrahydro-3-furancarboxylate

A solution of tert-Butyl(1S)-1-[(2S)-oxiran-2-yl]-2-phenylethylcarbamate(10.0 g, 38.0 mmol) and diethyl malonate (9.0 ml, 59.3 mmol) in ethanol(27 mL) at 0° C. was treated with a solution of NaOEt (16 mL, 21% inethanol) over 10 minutes, stirred at 70° C. for 2 hours, cooled to 0° C.and quenched with 10% citric acid solution, and partitioned betweenethyl acetate and water. The organic phase was washed with saturatedNaHCO₃and brine, dried over MgSO₄, filtered and concentrated. Theresidue was chromatographed on silica gel eluting with 0-35% ethylacetate in hexanes to give the title compound (13.3 g, 93% yield).

EXAMPLE 107Btert-butyl(1S)-1-{(2R)-5-oxo-4-[4-(2-pyridinyl)benzyl]tetrahydro-2-furanyl}-2-phenylethylcarbamate

A solution of the product from Example 107A (13.3 g, 35.27 mmol) inethanol (140 mL) at 0° C. was treated with a solution of NaOEt (14.9 mL,21% in ethanol) and solid 2-[4-(bromomethyl)phenyl]pyridine (12.05 g,48.59 mmol), stirred at 25° C. for 16 hours, treated with a solution ofLiOH monohydrate (8.9 g, 212.11 mmol) in water (35 mL), stirred at 25°C. for 5 hours, cooled to 0° C., adjusted to pH 5 by addition of 10%citric acid and then partitioned between dichloromethane and water. Theorganic phase was washed with brine and dried over MgSO₄, filtered andconcentrated. A solution of the concentrate in toluene (1 L) was heatedat reflux for 16 hours, cooled and concentrated to give the titlecompound (10.55 g, 63% yield), which was used without furtherpurification.

EXAMPLE 107C(4R,5S)-5-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(dimethyl)silyl]oxy}-6-phenyl-2-[4-(2-pyridinyl)benzyl]hexanoicacid

A solution containing the product from Example 107B (10.55 g, 22.35mmol) in a mixture of dioxane (130 mL) and water (65 mL) was treatedwith sodium hydroxide solution (33.5 mL, 1N), stirred for 30 minutes at25° C., concentrated, cooled to 0° C., acidified to pH 5 using 10%citric acid, and partitioned between dichloromethane and water. Theorganic phase layer was washed with brine, dried over Na₂SO₄, filteredand concentrated. A solution of the concentrate in dimethylformamide(130 mL) was treated with imidazole (18.3 g, 268.80 mmol) andt-butyldimethylsilyl chloride (20.2 g, 134.01 mmol), stirred at 25° C.for 16 hours, and concentrated. The concentrate was combined with iceand extracted with ethyl acetate. The organic phase was washed with 10%citric acid and brine, dried over MgSO₄, filtered, and concentrated. Asolution of the residue in a mixture of THF (100 mL), acetic acid (100mL) and water (33 mL) was stirred at 25° C. for 2 hours, andconcentrated under reduced pressure. The residue was dissolved intoluene and concentrated several times, followed by drying under highvacuum to give the title compound, which was used without furtherpurification.

EXAMPLE 107Dbenzyl(3R,4S)-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentylcarbamate

A solution of the product from Example 107C (22.35 mmol) in toluene (500mL) was treated with DPPA (5.3 mL, 24.59 mmol) and triethylamine (3.75mL, 26.90 mmol) was heated at reflux for 2 hours, cooled to 25° C.,treated with benzyl alcohol (6.9 mL, 66.68 mmol), heated at reflux foran additional 16 hours, cooled and concentrated. A solution of theconcentrate in THF (100 mL) was treated with TBAF solution in THF (67mL, 1N), stirred at 25° C. for 40 hours, concentrated, and partitionedbetween ethyl acetate and water. The organic phase was washed withbrined, dried over MgSO₄, filtered and concentrated, to give the titlecompound (4.98 g, 37% yield), which was used without furtherpurification.

EXAMPLE 107Etert-butyl(1S,2R)-4-amino-1-benzyl-2-hydroxy-5-[4-(2-pyridinyl)phenyl]pentylcarbamate

A solution containing the product from Example 107D (0.5 g, 0.840 mmol)in a mixture of methanol (4 mL) and ethyl acetate (4 mL) was treatedwith Pd(OH)₂ on carbon (0.175 g, 20% Pd by wt.) and HCl solution (0.40mL, 4N in dioxane), stirred under a hydrogen atmosphere (balloonpressure) at 25° C. for 2 hours, filtered through a bed of celite®,rinsed with methanol, and concentrated to give the title compound as thehydrochloride salt.

EXAMPLE 107Ftert-butyl(1S,2R,4S)-1-benzyl-2-hydroxy-4-({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-5-[4-(2-pyridinyl)phenyl]pentylcarbamate

A solution containing the product from Example 107E (0.840 mmol) in THF(8 mL) was treated with the product from Example 1F (0.175 g, 0.926mmol), DEPBT (0.375 g, 1.194 mmol), and N,N-diisopropylethylamine (0.75mL, 4.31 mmol), stirred at 25° C. for 16 hours, and partitioned betweenethyl acetate and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with0-100% ethyl acetate/dichloromethane to give a mixture of products(0.254 g, 48% yield). A portion of the mixture (0.112 g) waschromatographed on silica gel eluting with 0-100% tert-butyl methylether/dichloromethane, to give the lower Rf compound (0.033 g).

EXAMPLE 107Gtert-butyl(1S,2R,4R)-1-benzyl-2-hydroxy-4-({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-5-[4-(2-pyridinyl)phenyl]pentylcarbamate

A solution containing the product from Example 107E (0.840 mmol) in THF(8 mL) was treated with the product from Example 1F (0.175 g, 0.926mmol), DEPBT (0.375 g, 1.194 mmol), and N,N-diisopropylethylamine (0.75mL, 4.31 mmol), stirred at 25° C. for 16 hours, and partitioned betweenethyl acetate and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with0-100% ethyl acetate/dichloromethane to give a mixture of products(0.254 g, 48% yield). A portion of the mixture (0.112 g) waschromatographed on silica gel eluting with 0-100% tert-butyl methylether/dichloromethane, to give the higher Rf compound (0.042 g).

EXAMPLE 107Hmethyl(1S)-1-[({(1S,3R,4S)-4-amino-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 107F (0.033 g, 0.052mmol) in dichloromethane (1 mL) was treated with trifluoroacetic acid (1mL), stirred at 25° C. for 1 hour, concentrated, and partitioned betweenethyl acetate and saturated NaHCO₃ solution. The organic phase waswashed with brine, dried over MgSO₄, filtered and concentrated.

EXAMPLE 107Imethyl(1S)-1-[({(1S,3R,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 107H (0.052 mmol) in THF(0.6 mL) was treated with the product from Example 10D (0.021 g, 0.063mmol), DEPBT (0.024 g, 0.078 mmol), and N,N-diisopropylethylamine (0.045mL, 0.261 mmol), stirred at 25° C. for 16 hours, and partitioned betweenethyl acetate and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with0-100% ethyl acetate/dichloromethane, followed by 0-5% methanol in ethylacetate, to give the title compound (0.024 g, 56% yield). ¹H NMR (300MHz, DMSO-d₆), δ ppm 0.71 (s, 6 H); 0.89 (m, 12 H), 1.25 (s, 1 H), 1.48(m, 1 H), 1.71 (m, 1 H), 2.46 (m, 3 H), 2.63 (m, 1 H), 2.74 (m, 1 H),2.98 (m, 3 H), 3.22 (m, 1 H), 3.50 (m, 5 H), 3.82 (m, 2 H), 4.02 (s, 1H), 4.20 (m, 1 H), 4.38 (m, 2 H), 4.91 (d, J=6.62 Hz, 1 H), 6.77 (d,J=9.93 Hz, 1 H), 7.06 (m, 5 H), 7.16 (d, J=7.72 Hz, 1 H), 7.26 (d,J=8.46 Hz, 1 H), 7.32 (m, 3 H), 7.69 (m, 1 H), 7.87 (m, 6 H), 8.64 (d,J=4.78 Hz, 1 H).

EXAMPLE 108methyl(1S)-1-[({(1R,3R,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 108Amethyl(1S)-1-[({(1R,3R,4S)-4-amino-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 107G (0.042 g, 0.066mmol) in dichloromethane (1 mL) was treated with trifluoroacetic acid (1mL), stirred at 25° C. for 1 hour, concentrated, and partitioned betweenethyl acetate and saturated NaHCO₃ solution. The organic phase waswashed with brine, dried over MgSO₄, filtered and concentrated.

EXAMPLE 108Bmethyl(1S)-1-[({(1R,3R,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 108A (0.066 mmol) in THF(0.7 mL) was treated with the product from Example 10D (0.027 g, 0.080mmol), DEPBT (0.030 g, 0.100 mmol), and N,N-diisopropylethylamine (0.057mL, 0.332 mmol), stirred at 25° C. for 16 hours, and partitioned betweenethyl acetate and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with0-100% ethyl acetate/dichloromethane, followed by 0-5% methanol in ethylacetate, to give the title compound (0.027 g, 49% yield). ¹H NMR (300MHz, DMSO-d₆), δ ppm 0.88 (d, J=1.10 Hz, 18 H), 1.25 (s, 1 H), 1.51 (m,2 H), 2.46 (s, 3 H), 2.75 (d, J=6.25 Hz, 2 H), 2.87 (m, 1 H), 3.05 (m, 2H), 3.23 (m, 1 H), 3.48 (m, 5 H), 3.84 (m, 2 H), 3.99 (s, 1 H), 4.14 (m,1 H), 4.36 (m, 2 H), 4.67 (d, J=5.52 Hz, 1 H), 6.81 (d, J=9.56 Hz, 1 H),7.02 (m, 5 H), 7.15 (d, J=7.72 Hz, 1 H), 7.30 (m, 4 H), 7.67 (m, 2 H),7.87 (m, 5 H), 8.64 (d, J=4.78 Hz, 1 H).

EXAMPLE 109methyl(1S,4S,6S,7S,10S)-7-benzyl-10-sec-butyl-1-tert-butyl-6-hydroxy-13-methyl-14-(2-methyl-1,3-thiazol-4-yl)-2,9,12-trioxo-4-[4-(2-pyridinyl)benzyl]-3,8,11,13-tetraazatetradec-1-ylcarbamateEXAMPLE 109A 4-(chloromethyl)-2-methyl-1,3-thiazole

A solution of thioacetamide (2.45 g, 32.6 mmol) in 2-propanol (130 mL)was treated with dichloroacetone (4.14 g, 32.6 mmol) and heated at 60°C. for 2 hours, cooled and concentrated under reduced pressure. Thesolid product was added cautiously to a saturated NaHCO₃solution (gasevolution) and the mixture was partitioned between chloroform andsaturated NaHCO₃. The organic phase was washed with water, dried overNa₂SO₄, filtered and concentrated. The residue was purified bychromatography on silica gel eluting with chloroform to give the titlecompound.

EXAMPLE 109B N-methyl(2-methyl-1,3-thiazol-4-yl)methanamine

An aqueous solution of methylamine (18 mL, 40%) was treated with theproduct from Example 109A (2.0 g, 13.5 mmol) in portions over 0.5 hours,stirred at 25° C. for 16 hours, and concentrated. The residue waschromatographed on silica gel eluting with 5% methanol in chloroform togive the title compound (1.23 g, 64% yield).

EXAMPLE 109Cmethyl(2S,3S)-3-methyl-2-{[(4-nitrophenoxy)carbonyl]amino}pentanoate

A solution of L-iso-leucine methyl ester hydrochloride (2.5 g, 13.75mmol) in dichloromethane (35 mL) at 0° C. was treated with 4-nitrophenylchloroformate (3.05, 15.13 mmol) and 4-methylmorpholine (3.2 mL, 29.11mmol), stirred at 25° C. for 64 hours, and partitioned betweendichloromethane and saturated NaHCO₃. The organic phase was washed withbrine and dried over MgSO₄, filtered and concentrated to give the titlecompound (4.19 g, 98% yield).

EXAMPLE 109Dmethyl(2S,3S)-3-methyl-2-[({methyl[(2-methyl-1,3-thiazol-4-yl)methyl]amino}carbonyl)amino]pentanoate

A solution containing the product from Example 109B (0.200 g, 1.4 mmol)in THF (6 mL) was treated with the product from Example 109C (0.415 g,1.4 mmol), triethylamine (0.196 mL, 1.4 mmol), and DMAP (0.020 g, 0.16mmol) at 25° C., stirred at reflux for 1 hour, cooled and concentrated.The residue was partitioned between ethyl acetate and 5% K₂CO₃. Theorganic phase was washed with brine and dried over Na₂SO₄, filtered andconcentrated to give the title compound (0.38 mg, 86% yield).

EXAMPLE 109E(2S,3S)-3-methyl-2-[({methyl[(2-methyl-1,3-thiazol-4-yl)methyl]amino}carbonyl)amino]pentanoicacid

A solution of the product from Example 109D (0.38 g, 1.2 mmol) indioxane (5 mL) was treated with an aqueous solution of lithium hydroxide(5.0 mL, 0.5 M), stirred for 0.5 hours at 25° C., treated with aqueousHCl (2.5 mL, 1 N), and partitioned between ethyl acetate and water. Theorganic phase was washed with brine and dried over Na₂SO₄, filtered andconcentrated to give the title compound.

EXAMPLE 109Fmethyl(1S,4S,6S,7S,10S)-7-benzyl-10-sec-butyl-1-tert-butyl-6-hydroxy-13-methyl-14-(2-methyl-1,3-thiazol-4-yl)-2,9,12-trioxo-4-[4-(2-pyridinyl)benzyl]-3,8,11,13-tetraazatetradec-ylcarbamate

A solution containing the product from Example 2C (0.025 g, 0.047 mmol)in THF (0.5 mL) was treated with the product from Example 109E (0.018 g,0.061 mmol), DEPBT (0.021 g, 0.071 mmol), and N,N-diisopropylethylamine(0.041 mL, 0.235 mmol), stirred at 25° C. for 2 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was chromatographed on silica geleluting with 0-100% ethyl acetate/dichloromethane, followed by 0-10%methanol in ethyl acetate, to give the title compound (0.030 g, 78%yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.78 (m, 16 H), 1.01 (m, 1 H),1.36 (m, 1 H), 1.50 (m, 2 H), 1.70 (m, 1 H), 2.61 (s, 3 H), 2.73 (m, 3H), 2.86 (s, 3 H), 3.49 (s, 3 H), 3.62 (m, 1 H), 3.83 (d, J=9.93 Hz, 1H), 3.98 (t, J=7.91 Hz, 1 H), 4.11 (m, 2 H), 4.43 (m, 2 H), 4.86 (d,J=5.88 Hz, 1 H), 6.19 (d, J=8.09 Hz, 1 H), 6.62 (d, J=9.56 Hz, 1 H),7.16 (m, 8 H), 7.31 (m, 1 H), 7.42 (d, J=9.19 Hz, 1 H), 7.77 (d, J=8.09Hz, 1 H), 7.85 (m, 4 H), 8.63 (d, J=4.78 Hz, 1 H).

EXAMPLE 110methyl(1S,4S,5S,7S,10S)-7-benzyl-10-sec-butyl-1-tert-butyl-5-hydroxy-13-methyl-14-(2-methyl-1,3-thiazol-4-yl)-2,9,12-trioxo-4-[4-(2-pyridinyl)benzyl]-3,8,11,13-tetraazatetradec-1-ylcarbamate

A solution containing the product from Example 23S (0.025 g, 0.047 mmol)in THF (0.5 mL) was treated with the product from Example 109E (0.018 g,0.061 mmol), DEPBT (0.021 g, 0.071 mmol), and N,N-diisopropylethylamine(0.041 mL, 0.235 mmol), stirred at 25° C. for 2 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was chromatographed on silica geleluting with 0-100% ethyl acetate/dichloromethane, followed by 0-10%methanol in ethyl acetate. The product was then purified by reversedphase chromatography on a C18 column eluting with 5-100% acetonitrile inwater (0.1% TFA). The product was partitioned between ethyl acetate andsaturated NaHCO₃, and the organic phase was washed with brine and driedover MgSO₄, filtered and concentrated to give the title compound (0.011g, 29% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.64 (d, J=6.62 Hz, 3H), 0.72 (t, J=7.35 Hz, 3 H), 0.83 (s, 9 H), 0.93 (m, 1 H), 1.28 (m, 2H), 1.49 (m, 2 H), 1.60 (m, 1 H), 2.61 (s, 3 H), 2.73 (m, 3 H), 2.84 (s,3 H), 3.50 (s, 3 H), 3.62 (m, 1 H), 3.91 (m, 2 H), 4.10 (m, 2 H), 4.41(m, 2 H), 4.80 (d, J=5.52 Hz, 1 H), 6.01 (d, J=8.46 Hz, 1 H), 6.76 (d,J=9.93 Hz, 1 H), 7.12 (m, 6 H), 7.31 (m, 3 H), 7.60 (m, 2 H), 7.86 (m, 4H), 8.63 (d, J=4.41 Hz, 1 H).

EXAMPLE 111methyl(1S)-1-[({(1S,3S,4S)-4-{[(2S)-2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

Method A

A solution containing the product from Example 2C (1.09 g, 2.05 mmol) inTHF (20 mL) was treated with the product from Example 70A (0.71 g, 2.45mmol), DEPBT (1.0 g, 3.34 mmol), and N,N-diisopropylethylamine (2.0 mL,11.5 mmol), stirred at 25° C. for 16 hours, and partitioned betweenethyl acetate and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with0-100% ethyl acetate/dichloromethane, followed by 1% methanol in ethylacetate to give the title compound (1.197g, 73% yield). ¹H NMR (300 MHz,DMSO-d₆), δ ppm 0.83 (s, 9 H), 0.89 (s, 9 H), 1.56 (m, 2 H), 2.33 (q,J=9.2 Hz, 1 H), 2.58 (dd, J=13.6, 8.8 Hz, 1H), 2.67 (m, 2H), 2.78 (dd,J=13.6, 3.3 Hz, 1H), 2.84 (m, 1 H), 2.94 (q, J=9.2 Hz, 1 H), 3.19 (m, 1H), 3.50 (s, 3 H), 3.67 (m, 1 H), 3.85 (d, J=9.93 Hz, 1 H), 4.09 (s, 1H), 4.19 (m, 2 H), 4.31 (s, 2 H), 4.55 (d, J=7.72 Hz, 1 H), 6.63 (d,J=9.56 Hz, 1 H), 7.07 (m, 5 H), 7.22 (d, J=8.5 Hz, 2 H), 7.29 (m, 4 H),7.36 (m, 2 H), 7.47 (d, J=9.56 Hz, 1 H), 7.85 (m, 3H), 7.89 (d, J=8.5Hz, 2 H ), 8.63 (d, J=4.78 Hz, 1 H).

Method B

EXAMPLE 111-1 (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetaldehyde

Phthalimidoacetaldehyde diethyl acetal (75 g, 284.8 mmol) was added inone portion to 450 mL of 2N HCl in a 1 L 3-necked round bottom flaskequipped with mechanical stirring. The suspension was heated to 70° C.By the time the internal temperature reached 70° C., the reactionmixture was clear and starting material was consumed as determined byHPLC. The reaction mixture was stirred at 70° C. for 30 minutes. Thereaction mixture was allowed to cool to ambient temperature withstirring overnight, at which time the solid product had precipitated.The reaction was diluted with 400 mL of water and mixed for 3 hours. Thesolid was filtered and washed with 1 L of water, air dried, and dried ina vacuum oven at ambient temperature with a nitrogen bleed to afford thetitle compound (46.5 g, 86.4% yield). ¹H NMR (CDCl₃): δ 9.65 (s, 1 H),7.94 (m, 2 H), 7.75 (m, 2 H), 4.58 (s, 2 H).

EXAMPLE 111-2 tert-butylN-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-methyl-L-valinate

A solution of the product of Example 111-1 (46.5 g, 246.0 mmol) intetrahydrofuran (900 mL) was treated with L-tert-leucine-t-butyl esterhydrochloride salt (66.1 g, 295.2 mmol, 1.2 equivalents) stirred at 20°C. for 2 hours, treated with sodium triacetoxyborohydrodride (78.2 g,369.0 mmol, 1.5 equivalents) portionwise over 5 minutes (slightlyexothermic), stirred at 20° C. for 2 hours, diluted with ethyl acetate(1 L) and washed with water (1 L). The organic layer was washed withwater (1 L), 10% NaHCO₃ (2×1 L) and brine (1 L). The organic layer wasdried over MgSO₄, filtered, and concentrated to afford the titlecompound (87 g, 98.2% yield). ¹H NMR (CDCl₃): δ 7.82 (m, 2 H), 7.70 (m,2 H), 3.77 (t, 2 H), 2.92 (m, 1 H), 2.73(s, 1H), 2.68(m, 1H), 1.44(s,9H), 0.86(s, 9H).

EXAMPLE 111-3 tert-butyl N-(2-aminoethyl)-3-methyl-L-valinate

The product of Example 111-2 (87 g, 241.6 mmol) was taken up in ethanol(2 L) in a 3-necked, 3L round bottom flask equipped with mechanicalstirring under N₂. Hydrazine (anhydrous, 68.3 mL, 2.17 mol, 9equivalents) was added. The reaction mixture was heated to 75° C., whichresulted in the formation of a very thick suspension. The addition ofmore ethanol was necessary in order to continue effective stirring. Thereaction was stirred for 1 hour at 75° C. until consumption of startingmaterial was complete as determined by HPLC. The thick suspension wascooled to ambient temperature and quenched with 1 L of 0.5N NaOHsolution. The mixture was diluted with 0.5N NaOH (2 L) and extractedwith dichloromethane (2×2 L). The combined organic layer was washed withbrine (1 L), dried over MgSO₄, filtered and concentrated to oil. The oilwas chased with heptanes to remove ethanol and pump dried to affordlight yellow oil (50.2 g, 93.2% yield). ¹H NMR (CDCl₃): δ 2.73(m, 4H),2.45(m, 1H), 1.64(s, 9H), 0.96(s, 9H).

EXAMPLE 111-4 tert-butyl N-[2-(benzylamino)ethyl]-3-methyl-L-valinate

A solution of benzaldehyde (23 g, 217 mmol) and the product of Example111-3 (50 g, 217 mmol, 1 equivalent) in 50:50 mixture of toluene andmethanol (total volume=1400 mL), stirred at 50° C. overnight, cooled to−3° C., treated with NaBH₄ (16.6 g, 434 mmol, 2equivalents) slowly over5 hours, and stirred at room temperature for 16 hours. The reactionmixture was quenched with a saturated NaHCO₃ solution (1400 mL) andextracted with ethyl acetate (1.3 L). The layers were separated and theaqueous layer was extracted with ethyl acetate (850 mL). The organiclayers were combined, washed with brine (900 mL), and concentrated. Theresidue was dissolved in heptanes (700 mL), decanted inorganic salt,distilled to oil and chased to yield 69.4 g of crude material. ¹H NMR(CDCl₃): δ 7.05-7.3(m, 7H), 3.75(d, 2H), 2.4-2.8(m, 5H), 1.4(s, 9H),0.87(s, 9H).

EXAMPLE 111-5tert-butyl(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoate

A solution of the product of Example 111-4 in 1,2-dichloroethane (1325mL) was treated with triethylamine (37.5 mL, 269 mmol, 1.25 equivalents)and N,N-disuccinimidyl carbonate (68.9 g, 269 mmol, 1.25 eq). Thereaction mixture was stirred at 20° C. overnight, washed with 10% Na₂CO₃(2×1.5 L). The aqueous was back-extracted with dichloromethane (600 mL).The organics were combined and washed with 1.5 L of brine. The organiclayer was concentrated to yield 76.8 gm of crude material. ¹H NMR(CDCl₃): δ 7.15-7.3(m, 5H), 4.25-4.4(m, 3H), 3.75(m, 1H), 3.67(residualdichloroethane), 3.48(m, 1H), 3.1(m, 2H), 1.4(s, 9H), 1.0(s, 9H).

EXAMPLE 111-6(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoic acid

To a solution of the product of Example 111-5 in dichloromethane (1.5 L)was added triflouroacetic acid (810 mL). The mixture was stirred at roomtemperature for 3 hours and concentrated. The residue was chased withheptanes (4×500 mL). The product was partitioned between dichloromethane(1.5 L) and 5% KH₂PO₄ (1.1 L). The organic layer was washed with 5%KH₂PO₄ (900 mL) and brine (900 mL), and concentrated. A solution of theresidue in dichloromethane (500 mL) was dried over MgSO₄, filtered andconcentrated. The residue was recrystallized twice from isopropylalcohol/water to afford the title compound. ¹H NMR (DMSO-d₆): δ7.2-7.4(m, 5H), 4.28(d, 2H), 4.21(s, 1H), 3.47-3.64(m, 2H), 3.08-3.2(m,2H), 1.0(s, 9H).

EXAMPLE 111-7 2-[4-(bromomethyl)phenyl]pyridine

A mixture of 2-(p-tolyl) pyridine (118.88 g, 702.5 mmol),N-bromosuccinimide (131.29 g, 737.6 mmol, 1.05 equivalents) and CCl₄(1190 mL) was treated with benzoyl peroxide (1.70 g, 7.03 mmol, 0.01equivalents) under nitrogen, stirred at 70° C. for 1.5 hours, and thenallowed to cool to ambient temperature with stirring overnight. Thereaction mixture was filtered, washed with CCl₄ (2×250 mL), concentratedto oil, treated with isopropyl alcohol (420 mL) and cooled to −5° C. Theresulting solid was filtered, washed with isopropyl alcohol (140 mL),and dried in a vacuum oven with a N₂ bleed to afford the title compound(111.91 g, 64.2% yield). ¹H NMR (CDCl₃): δ 8.70(m, 1H), 7.99(m, 2H),7.75(m, 2H), 7.52(m, 2H), 7.25(m, 1H), 4.58 (s, 2H).

EXAMPLE 111-8tert-butyl(1S)-1-[(2S)-5-oxo-4-(4-pyridin-2-ylbenzyl)tetrahydrofuran-2-yl]-2-phenylethylcarbamate

450 g of tert-Butyl (1S)-1-[(2R)-oxiran-2-yl]-2-phenylethylcarbamate wastreated with 1.1 equivalents of diethyl malonate and 1.05 equivalents ofsodium ethoxide in 1200 mL of ethanol at 5° C. for 0.5 hr, then at 25°C. for 5 hrs. The reaction mixture was quenched with acetic acid tillthe pH of the mixture was about 6. The reaction mixture was extractedwith ethyl acetate (4 L) and the isolated organic phase was washedsequentially with 25% brine (4 L), 5% NaHCO₃ (5L), and 25% brine (4 L),dried over NaSO₄, filtered, concentrated and chased with 2 L of methyltert-butyl ether to dryness. The oil was dissolved in 950 mL of methyltert-butyl ether and warmed to 45° C., added heptane (4L) and cooled to−5° C. The solid was isolated by filtration to providetert-butyl(1S)-1-[(2S)-5-oxotetrahydrofuran-2-yl]-2-phenylethylcarbamate.A mixture of the tert-butyl(1S)-1-[(2S)-5-oxotetrahydrofuran-2-yl]-2-phenylethylcarbamate (400 g,1.028 mol), the product of Example 111-7 (321 g, 1.08 mol, 1.05equivalents) in absolute ethanol (3.35 L) was cooled to 5° C. wastreated with a solution of sodium ethoxide (77.5 g sodium ethoxide in0.65 L of absolute ethanol, 1.05 equivalents) over 1 hour. The reactionmixture was stirred at 3° C. for 3 hours. Lithium hydroxide monohydrate(215.6 g, 5.138 mol, 5 equivalents) was added all at once and thetemperature rose to 10° C. The mixture was stirred at 10° C. for 2hours, treated with acetic acid (308.6 gm, 5.138 mol, 5 eq) and stirredat 60° C. for 17 hours. The reaction mixture was treated with distilledwater (4 L) over 20 minutes while maintaining the internaltemperature >55° C. The slurry was cooled slowly to 14° C. over 2.5hours, filtered, washed with 1:1 ethanol:water (total volume=2 L),heptanes (2 L) and dried at 55° C. vacuum oven under N₂ for 40 hours togive the title compound (451.9 g, 91% yield). ¹H NMR (CDCl₃): δ 8.65(m,1H), 7.90(m, 2H), 7.65-7.75 (m, 2H), 7.17-7.30(m, 8H), 4.63(m, 1H),4.32(m, 1H), 3.95(m, 1H), 3.32(m, 1H), 2.7-3.0(m, 4H), 2.10 (m, 1H),1.74(m, 1H), 1.36 (s, 9H).

EXAMPLE 111-9(4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(dimethyl)silyl]oxy}-6-phenyl-2-(4-pyridin-2-ylbenzyl)hexanoicacid

A solution of the product of Example 111-8 (250 g, 529 mmol) inN-methylpyrrolidinone (2L) under N₂ was treated with milled lithiumhydroxide monohydrate (33.3 g, 793.5 mmol, 1.5equivalents) andN,N-(dimethylamino)pyridine (6.5 g, 53 mmol, 0.1 equivalent) and stirredat 40° C. for 10 hrs. The reaction mixture was cooled to about 22° C.,treated with imidazole (827.5 g, 12.2 mol, 23 equivalents) over 15minutes, stirred at 22° C. for 30minutes, cooled to 6° C., and treatedwith t-butyldimethylsilyl chloride (876.94 g, 5.819 mol, 11 equivalents)over 45 minutes. This mixture was warmed to 22° C., stirred at 20° C.for 1.5 hours, and stirred at 40° C. overnight. The reaction mixture wascooled to 22° C., charged with 1.25 L of distilled water over 10 minutesand mixed for 2 hrs. The reaction mixture was charged with 1.25 L ofbrine, 1.25 L of ethyl acetate and 1.25 L of heptanes. The aqueous layerwas extracted with 1.25 L of ethyl acetate and 1.25 L of heptanes. Thecombined organic layer was washed with brine (2×1.2 L), concentrated andchased with heptanes (1.4 L). The resulting oil was dissolved inN,N-dimethylformamide (812 mL), partitioned between heptanes (5.25 L)and 10% aqueous K₂CO₃ (1.25 L). The heptane layer was extracted with 10%K₂CO₃ (2×400 mL) and N,N-dimethylformamide (260 mL). The combinedaqueous layer (DMF/K₂CO₃) was washed with 4×5L heptanes. The aqueouslayer was cooled to 5° C., charged with 2.5L of toluene, adjusted to pH5 with 5% HCl, and extracted with 1.6 L of toluene. The combined toluenelayer was washed with brine (2×1.75 L), and water (2×1.75 L),concentrated to oil and chased with toluene (2×800 mL) to give the titlecompound. ¹H NMR (CDCl₃): δ 8.50(m, 1H), 7.5-7.8(m, 4H), 7.0-7.2 (m,8H), 4.6 (m, 1H), 3.6-4.0(m, 2H), 2.5-2.9(m, 4H), 2.25(s, residualtoluene), 1.5-2.0(m, 2H), 1.0-1.3 (s+d, boc), 0.85(s, t-butyl), 0 (m,6H).

EXAMPLE 111-10Benzyl(3S,4S)-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentylcarbamate

To the product of Example 111-9 (274 g, 453 mmol) in toluene (2.65 L)were added triethylamine (126.5 mL, 906 mmol, 2 equivalents) and DPPA(128.5 g, 453 mmol, 1 equivalent). The mixture was stirred at 40° C. for1 hour. Additional DPPA (6.3 mL, 17 mmol, 0.04 equivalent) was chargedto the reaction mixture and mixed at 40° C. for 3 hours. Benzyl alcohol(147 g, 1.359 mol, 3 equivalents) was added and the mixture was heatedat 105° C. for 10 hours then 22° C. for 7 hours. The reaction mixturewas washed with 10% Na₂CO₃ (1.1 L), saturated NaHCO₃ (1.1 L), and water(4×3 L). The organic layer was concentrated. The residue was dissolvedin tetrahydrofuran (500 mL), cooled to 5° C. and treated with 1M TBAF intetrahydrofuran (2.5 L, 5.5 equivalents.) and the mixture was stirred at5° C. for 2 hrs. The reaction mixture was quenched with 5% KH₂PO₄ (2.6L) and water (1.1 L), extracted with ethyl acetate (5 L). The aqueouslayer was extracted with ethyl acetate (3.2 L). The combined organiclayers were washed with water (3×2.7 L) and concentrated. The resultingsolid was chased with heptanes and methanol. The solid was dissolved inmethanol (1.6 L) at 63° C., cooled to 22° C. and stirred at 22° C. untilsolids precipitated. The slurry was treated with 800 mL of distilledwater, mixed at 22° C. for 3 hours, filtered, washed with 2:1methanol:water (total volume=600 mL), and heptanes (700 mL). The wetcake was dried in 50° C. vacuum oven under N₂ to give the title compound(diastereomeric ratio=1.3:1 as determined by HPLC (Column: Zorbax C-8 25cm, flow, Gradient system: 0-5 min, 0.1% H₃PO₄/10% CH₃CN/90% water to0.1% H₃PO₄/90% CH₃CN/10% water, 5-12 hold at 0.1% H₃PO₄/90% CH₃CN/10%water, 12-13 min, 0.1% H₃PO₄/90% CH₃CN/10% water to 0.1% H₃PO₄/10%CH₃CN/90% water, 13-15 min, hold at 0.1% H₃PO₄/10% CH₃CN/90% water). ¹HNMR (DMSO-d₆): δ 8.64(m, 1H), 7.81-7.97(m, 4H), 7.10-7.33(m, 14H),6.27(m, 1H), 4.83-4.95(m, 2H), 4.60(d, 1H), 3.95(m, 1H), 3.80(m, 1H),3.55(m, 1H), 2.57-2.77(m, 4H), 1.55(m, 2H), 1.27(s, 9H).

EXAMPLE 111-11Benzyl(3S,4S)-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentylcarbamate

A mixture of the product of Example 111-10 (12 g, 20 mmol), ammoniumformate (5.1 g, 81 mmol, 4 equivalents) and methanol (360 mL) wastreated with Pd/C (4.8 gm, 40% loading) and stirred at ambienttemperature under N₂ for 1.5 hr, filtered and concentrated. A solutionof the residue in dichloromethane (150 mL) was washed with saturatedNaHCO₃ (2×80 mL), and brine (2×50 ml). The dichloromethane layer wasdried over Na₂SO₄ filtered and concentrated to give the title compound(8.75 g, 93% yield). ¹H NMR (DMSO-d₆): δ 8.61(m, 1H), 7.96(d, 2H),7.89(d, 1H), 7.82(m, 1H), 7.10-7.32(m, 8H), 6.25(d, 1H), 3.65(m, 1H),3.55(m, 1H), 2.98(m, 1H), 2.51-2.81(m, 4H), 1.44(m, 1H), 1.15-1.35(s+s,10H).

EXAMPLE 111-12tert-butyl(1S,2S)-1-benzyl-2-hydroxy-4-({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-5-[4-(2-pyridinyl)phenyl]pentylcarbamate

A mixture of (2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoic acid(Degussa, 8.74 g, 46.18 mmol, 1.1 equivalents), K₂CO₃ (11.60 g, 83.96mmol, 2equivalents), DEPBT (15.08 g, 50.38 mmol, 1.2 equivalents) inethyl acetate (400 mL) was stirred at room temperature under N₂ for 1hour, treated with the product of Example 111-11 (20 g, 41.98 mmol) andstirred at room temperature under N₂ for 24 hrs. The reaction mixturewas washed with H₂O (200 mL), 10% NaHCO₃ (200 mL), and H₂O (2×200 mL).The organic layer was concentrated, and the residue charged with ethylacetate (30 mL), heated to 70° C. for 1 hr, added heptanes (120 mL)dropwise, stirred at 70° C. for 30 minutes, cooled to room temperatureovernight. The slurry was filtered and washed with 100 mL of 1:1heptane/ethyl acetate, and dried in 50° C. vacuum oven overnight to givethe title compound.

EXAMPLE 111-13Atert-butyl(1S,2S,4R)-1-benzyl-2-hydroxy-4-({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-5-[4-(2-pyridinyl)phenyl]pentylcarbamate

A 12 L 3-necked round bottom flask was charged with 169.74 gm of theproduct of Example 111-12 and 3.5 L of methanol, warmed to 45° C., water(1.75 L) was slowly added, stirred at 45-48° C. for about 1 hour, andcooled to ambient temperature overnight. The slurry was filtered andwashed with 2:1 methanol:water, suction dried for 1 hour and dried at50° C. vacuum oven overnight to give 60.4 gm of the title compound (28:1diastereomeric ratio as determined by HPLC (Column: XDB C8 15 cm,Eluent: CH₃CN/10 mM Na₂HPO₄ with H₃PO₄ adjusted to pH 7, Gradient: 10%CH₃CN to 90% CH₃CN in 15 min, then hold for 10 min, column oventemperature: 35° C.).

EXAMPLE 111-13Btert-butyl(1S,2S,4S)-1-benzyl-2-hydroxy-4-({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-5-[4-(2-pyridinyl)phenyl]pentylcarbamate

The 7.6 L mother liquor from Example 111-13A was heated to 45° C. in a12 L 3-necked flask, water (2.37 L) was added dropwise to make a 1:1methanol:water solution, stirred at 45° C. for 2 hours, and cooled toambient temperature overnight. The slurry was filtered, dried in 50° C.vacuum oven overnight to give 99.52 gm of the title compound (27:1diastereomeric ratio as determined by HPLC (Column: XDB C8 15 cm,Eluent: CH₃CN/10 mM Na₂HPO₄with H₃PO₄ adjusted to pH 7, Gradient: 10%CH₃CN to 90% CH₃CN in 15 min, then hold for 10 min, column oventemperature: 35° C.). ¹H NMR (CDCl3): δ 8.66(m, 1H), 7.90(d, 2H),7.65-7.76(m, 2H), 7.11-7.24(m, 8H), 5.74(d, 1H), 5.22 (d, 1H), 4.95(d,1H), 4.27-4.45(m, 2H), 3.60-3.73(m, 5H), 3.47(m, 1H), 2.70-2.98(m, 4H),1.82-1.93(m, 1H), 1.25-1.45(m, 10H), 0.75(s, 9H).

EXAMPLE 111-14methyl(1S)-1-[({(1S,3S,4S)-4-amino-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A suspension of the product of Example 111-13B (113.8 mmol) in isopropylacetate 1050 mL was treated with concentrated HCl (72 mL, 869 mmol, 8equivalents) and stirred at ambient temperature for 1 hour. The reactionmixture was charged with water (360 mL) and heptanes (900 mL) and thelayers separated. The organic layer was extracted with water (360 mL).The combined aqueous layers was washed with 1:1 isopropylacetate:heptanes (2×500 mL). The aqueous layer was charged with ethylacetate (360 mL), cooled to <10° C., and adjusted the pH to 9 with 77 gof Na₂CO₃ while keeping the temperature at <10° C. and the layersseparated. The aqueous layer was extracted with ethyl acetate (720 mL).The combined ethyl acetate layers was washed with saturated NaHCO₃ (350mL), and brine (2×350 mL), dried over Na₂SO₄ filtered and concentratedto give the title compound. ¹H NMR (DMSO-d₆): δ 8.62(m, 1H),7.81-7.97(m, 5H), 7.12-7.33(m, 9H), 6.87(d, 1H), 4.51(d, 1H), 4.15 (m,1H), 3.80(d, 1H), 3.55(s, 3H), 2.60-2.84(m, 4H), 2.40(m, 1H), 1.65 (m,1H), 1.50(m, 1H), 0.73(s, 9H).

EXAMPLE 111-15methyl(1S)-1-[({(1S,3S,4S)-4-{[(2S)-2-(3-benzyl-2-oxo-1-imidazolinyl)-3,3-dimethylbutanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A mixture of the product of Example 111-6 (30.7 g, 105.8 mmol, 1equivalent), K₂CO₃ (29.2 g, 211.6 mmol, 2 equivalents), ethyl acetate(270 mL) and DEPBT (33.2 g, 299.23 mmol, 1.05 equivalent) was stirred at20° C. for 30 minutes, treated with the product of Example 111-14 (56.4g, 105.8 mmol) and stirred at 20° C. for 5 hours. Additional Example1116 (4 g, 0.13 equivalent), DEPBT (6.4 g, 0.2 equivalent), K₂CO₃ (2.7g, 0.18 equivalent) were added and the mixture was stirred at 20° C.overnight. The reaction mixture was quenched with water (300 mL), washedwith 10% Na₂CO₃ (3×480 mL), 5% KH₂PO₄ (2×480 mL), and brine (480 mL),dried over Na₂SO₄, filtered and concentrated. The residue wascrystallized from ethyl acetate (420 mL)/heptanes (840 mL) to provide 84gm of the ethyl acetate solvate of the title compound. ¹H NMR (DMSO-d₆):δ 8.60(m, 1H), 7.85(m, 5H), 7.45 (m, 1H), 7.2-7.4 (m, 8H), 7.1 (m, 2H),7.0(m, 3H), 6.6(d, 1H), 4.5(d, 1H), 4.3(d, 2H), 4.15(m, 2H), 4.07(s,1H), 3.85(d, 1H), 3.65(m, 1H), 3.49(s, 3H), 3.17(m, 1H), 2.93(q, 1H),2.8(m, 2H), 2.66(d, 2H), 2.57(m, 1H), 2.33(q, 1H), 1.55(m, 2H), 0.88 (s,9H)), 0.82(s, 9H).

The ethyl acetate solvate of the title compound (90 g, 89.5 g by assay)was dissolved in 450 mL isopropyl alcohol, then charged with 1350 mLwater to crystallize the desired compound. After filtration and drying,85.3 g of the hydrate of the title compound was obtained.

EXAMPLE 1121,2,5,6-tetradeoxy-2,5-bis({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-1,6-bis[4-(2-pyridinyl)phenyl]-L-iditolEXAMPLE 112Amethyl(2S)-3-(4-bromophenyl)-2-[(tert-butoxycarbonyl)amino]propanoate

A mixture of (L)-4-bromophenylalanine (1.0 g, 4.1 mmol), NaHCO₃ (0.9 g,10.7 mmol), and di-tert-butyldicarbonate (1.34 g, 6.1 mmol) in 4:11,4-dioxane:water (25 mL) was stirred at 25° C. for 18 hours, dilutedwith water (20 mL) and extracted with dichloromethane (50 mL). Theaqueous phase was adjusted to pH 2 using 1N HCl, and extracted withethyl acetate (2×50 mL). The combined organic phase was dried overNa₂SO₄, filtered and concentrated. A solution of the concentrate inmethanol (20 mL) was cooled to 0° C., treated with a solution oftrimethylsilyl diazomethane (2.0 M in Et₂O), stirred at 25° C. for 18hours, then concentrated. The residue was chromatographed on silica gel,eluting with dichloromethane to afford the title compounds (1.15 g,78%).

EXAMPLE 112Btert-butyl(1S)-2-hydroxy-1-[4-(2-pyridinyl)benzyl]ethylcarbamate

(i) A solution containing the product from Example 112A (1.15 g, 3.2mmol) in anhydrous THF (20 mL) at 0° C. was treated dropwise with asolution of lithium aluminumhydride (3.2 mL, 1N in THF), stirred at 0°C. for 1 h, treated with ethyl acetate (2 mL), washed with water (10mL), 15% aq. NaOH, and water (10 mL), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography onsilica gel, eluting with 30-50% ethyl acetate in hexanes.

(ii) A solution of the product from step (i) (0.20 g, 0.61 mmol),3-tri-n-butylstannyl)pyridine (0.9 g, 2.44 mmol), anddichlorobis(triphenylphosphine)palladium (0.13 g, 0.19 mmol) in dryacetonitrile (4 mL) was stirred at 80° C. for 18 hours, filtered andconcentrated. The concentrate was chromatographed on silica gel, elutingwith 30-60% ethyl acetate in hexanes to give the title compound (0.18 g,90%).

EXAMPLE 112C2,5-bis[(tert-butoxycarbonyl)amino]-1,2,5,6-tetradeoxy-1,6-bis[4-(2-pyridinyl)phenyl]-L-iditol

(i) A solution of oxalyl chloride (0.42 mL, 2.0 M in CH₂Cl_(2,)0.84mmol) in anhydrous dichloromethane (2 mL) at −63° C. (CHCl₃-dry icebath) was treated dropwise with a solution of DMSO (80 μL, 88 mg, 1.13mmol) in dichloromethane (2 mL). To this solution was added dropwise asolution of the product from Example 112B (0.18 g, 0.55 mmol) inanhydrous dichloromethane (1 mL). The resulting mixture was stirred for20 min at 63° C., treated with triethylamine (0.31 mL, 0.23 g, 2.22mmol), stirred for 30 min at −63° C., warmed to 25° C., treated with 10%citric acid (5 mL) and hexanes (5 mL), and the layers were separated.The aqueous layer was washed with diethyl ether (2×5 mL). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated. Thecrude product was purified by column chromatography on silica gel,eluting with 1:1 ethyl acetate: hexanes to give the aldehyde (0.12 g,67%).

(ii) A solution of vanadium (III) chloride-THF complex (1:3) inanhydrous CH₂Cl₂ (0.5 M, 0.4 mL, 0.2 mmol) under N₂ was treated with Zn(7 mg, 0.11 mmol), stirred at 25° C. for 30 min. To this mixture wasadded a solution of the aldehyde from step (i) (60 mg, 0.20 mmol) inanhydrous dichloromethane (0.5 mL), and the resulting mixture wasstirred at 25° C. for 18 hours. The mixture was treated with 0.2 M HCl(2 mL), stirred at 25° C. for 1 h, extracted with dichloromethane (3×2mL), dried over Na₂SO₄, filtered and concentrated. The crude product waschromatographed on silica gel, eluting 60-100% ethyl acetate in hexanesto give the title compound (11 mg, 9%).

EXAMPLE 112D1,2,5,6-tetradeoxy-2,5-bis({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-1,6-bis[4-(2-pyridinyl)phenyl]-L-iditol

A solution of the product from Example 112C (9 mg, 14 μmol) in a 1:1mixture of methanol and 4N HCl (0.2 mL) was stirred at 25° C. for 4hours, and concentrated in vacuo. A solution of the residue indimethylformamide (0.2 mL) was treated with the product from Example 1F(7 mg, 40 μmol), DEPBT (18 mg, 60 μmol), and triethylamine (12 μL, 9 mg,86 μmol), stirred at 25° C. for 18 hours, and partitioned betweensaturated NaHCO₃ (0.5 mL) and ethyl acetate (3×1 mL). The organic phasewas dried over Na₂SO₄ filtered and concentrated. The residue waschromatographed on silica gel, eluting with 50-100% ethyl acetate inhexanes to afford the title compound (6 mg, 55%).

1H NMR (300 MHz, CDCl₃) δ ppm 0.81(s, 18H), 3.02(m, 4H), 3.49 (m, 2H),3.59(s, 6H), 3.74(m, 2H), 4.14(m, 4H), 5.19(m, 2H), 6.33(m, 2H), 7.34(d, J=8.09 Hz, 4H), 7.74(m, 6H), 7.88(d, J=8.46 Hz, 4H), 8.67(m, 2H).

EXAMPLE 113methyl(1S)-1-[({(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-1-[4-(6-methoxy-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 113A methyl 6-(tributylstannyl)-2-pyridinyl ether

A solution containing 2-bromo-6-methoxypyridine (0.65 mL, 5.3 mmol) inether (11 mL) at −78° C. was treated with n-butyllithium (4.0 mL, 1.6 Min hexanes) dropwise, warmed to 0° C. for 10 minutes, cooled to −78° C.,treated with tributyltin chloride (2.25 mL, 8.30 mmol), stirred at −78°C. for 0.5 hours, and then at 0° C. for 0.5 hours. The reaction wasquenched with saturated ammonium chloride solution and partitionedbetween ether and water. The organic phase was washed with brine anddried over MgSO₄, filtered and concentrated to give the title compound.

EXAMPLE 113Bbenzyl(1S,3S,4S)-4-[(tert-butoxycarbonyl)amino]-3-{[tert-butyl(dimethyl)silyl]oxy}-1-[4-(6-methoxy-2-pyridinyl)benzyl]-5-phenylpentylcarbamate

A solution containing the product from Example 92D (0.20 g, 0.28 mmol)in DMF (3 mL) was treated with LiCl (0.119 g, 2.8 mmol),dichlorobis(triphenylphosphine)palladium(II) (0.060 g, 0.085 mmol), andthe product from Example 113A (0.336 g, 0.84 mmol), heated at 100° C.for 16 hours, cooled, filtered through celite®, and partitioned betweenethyl acetate and water. The organic phase was washed with brine anddried over MgSO₄, filtered and concentrated to give the title compound.

EXAMPLE 113Cbenzyl(1S,3S,4S)-4-[(tert-butoxymethyl)amino]-3-hydroxy-1-[4-(6-methoxy-2-pyridinyl)benzyl]-5-phenylpentylcarbamate

The product from Example 113B (0.28 mmol) was treated with TBAF solutionin THF (1.4 mL, 1N), stirred at 25° C. for 16 hours, concentrated andpartitioned between ethyl acetate and water. The organic phase waswashed with brined, dried over MgSO₄, filtered and concentrated. Theresidue was chromatographed on silica gel eluting with 20% ethyl acetatein dichloromethane, to give the title compound (0.055 g, 31% yield).

EXAMPLE 113Dbenzyl(1S,3S,4S)-4-amino-3-hydroxy-1-[4-(6-methoxy-2-pyridinyl)benzyl]-5-phenylpentylcarbamate

A solution of the product from Example 113C (0.093 g, 0.15 mmol) in THF(1 mL) was treated with an HCl solution (0.26 mL, 4 N in dioxane),stirred at 25° C. for 64 hours, and concentrated. The concentrate wastreated with ethanol and concentrated several times to give the titlecompound as the hydrochloride salt.

EXAMPLE 113Ebenzyl(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-1-[4-(6-methoxy-2-pyridinyl)benzyl]-5-phenylpentylcarbamate

A solution containing the product from Example 113D (0.049 mmol) in THF(0.5 mL) was treated with the product from Example 10D (0.017 g, 0.049mmol), DEPBT (0.030 g, 0.099 mmol), and N,N-diisopropylethylamine (0.043mL, 0.246 mmol), stirred at 25° C. for 5 hours, and partitioned betweenchloroform and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated.

EXAMPLE 113F(2S)-N-{(1S,2S,4S)-4-amino-1-benzyl-2-hydroxy-5-[4-(6-methoxy-2-pyridinyl)phenyl]pentyl}-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanamide

A solution containing the product from Example 113E (0.049 mmol) inmethanol (1 mL) was treated with Pd on carbon (0.005 g, 10% Pd by wt.)and HCl solution (0.050 ML, 4N in dioxane), stirred under a hydrogenatmosphere (balloon pressure) at 25° C. for 16 hours, filtered through abed of celite®, rinsed with methanol, and concentrated to give the titlecompound as the hydrochloride salt.

EXAMPLE 113Gmethyl(1S)-1-[({(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-1-[4-(6-methoxy-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 113F (0.049 mmol) in THF(0.5 mL) was treated with the product from Example 1F (0.010 g, 0.054mmol), DEPBT (0.029 g, 0.098 mmol), and N,N-diisopropylethylamine (0.043mL, 0.245 mmol), stirred at 25° C. for 16 hours, and partitioned betweenchloroform and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with2% methanol in chloroform. The product was purified by reversed phasechromatography on a C18 column eluting with 20-100% acetonitrile inwater (0.1% TFA). The product was partitioned between ethyl acetate andsaturated NaHCO₃, and the organic phase was washed with brine and driedover MgSO₄, filtered and concentrated to give the title compound (0.0065g, 16% yield). ¹NMR (300 MHz, CDCl₃) δ ppm 0.94(s, 9H), 0.98(s, 9H),1.77-1.63(m, 2H), 2.69-2.59(m, 1H), 2.59(bs, 3H), 2.86-2.80(m, 4H),3.21-3.04(m, 2H), 3.41-3.34(m, 1H), 3.62(s, 3H), 3.77-3.72(m, 2H),4.02(s, 1H), 4.03(s, 3H), 4.34-4.16(m, 2H), 4.64-4.46(m, 2H),5.36-5.34(d, J-7.72 Hz, 1H), 6.04-6.01(d, J=7.35 Hz, 1H), 6.43-6.40(d,J=8.82 Hz, 1H), 6.68-6.66(d, J=7.72 Hz, 1H), 7.33-7.09(m, 10H),7.64-7.59(m, 2H), 7.95-7.92(d, J=8.09 Hz, 2H).

EXAMPLE 114methyl(1S)-1-[({(1S,3S,4S)-4-{[(2S)-2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-3-hydroxy-1-[4-(6-methoxy-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 114Abenzyl(1S,3S,4S)-4-{[(2S)-2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-3-hydroxy-1-[4-(6-methoxy-2-pyridinyl)benzyl]-5-phenylpentylcarbamate

A solution containing the product from Example 113D (0.049 mmol) in THF(0.5 mL) was treated with the product from Example 70A (0.016 g, 0.055mmol), DEPBT (0.030 g, 0.099 mmol), and N,N-diisopropylethylamine (0.043mL, 0.246 mmol), stirred at 25° C. for 5 hours, and partitioned betweenchloroform and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated.

EXAMPLE 114B(2S)-N-{(1S,2S,4S)-4-amino-1-benzyl-2-hydroxy-5-[4-(6-methoxy-2-pyridinyl)phenyl]pentyl}-2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanamide

A solution containing the product from Example 114A (0.049 mmol) inmethanol (1 mL) was treated with Pd on carbon (0.005 g, 10% Pd by wt.)and HCl solution (0.050 mL, 4N in dioxane), stirred under a hydrogenatmosphere (balloon pressure) at 25° C. for 3 hours, filtered through abed of celite®, rinsed with methanol, and concentrated to give the titlecompound as the hydrochloride salt.

EXAMPLE 114Cmethyl(1S)-1-[({(1S,3S,4S)-4-{[(2S)-2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-3-hydroxy-1-[4-(6-methoxy-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 114B (0.049 mmol) in THF(0.5 mL) was treated with the product from Example 1F (0.010 g, 0.054mmol), DEPBT (0.029 g, 0.098 mmol), and N,N-diisopropylethylamine (0.043mL, 0.245 mmol), stirred at 25° C. for 16 hours, and partitioned betweenchloroform and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with2% methanol in chloroform. The product was purified by reversed phasechromatography on a C18 column eluting with 40-100% acetonitrile inwater (0.1% TFA). The product was partitioned between ethyl acetate andsaturated NaHCO₃, and the organic phase was washed with brine and driedover MgSO₄, filtered and concentrated to give the title compound (0.0065g, 16% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm 0.94(s, 9H), 0.98(s, 9H),1.77-1.63(m, 2H), 2.64-2.55(q, J=9.19 Hz, 1H), 2.95-2.81(m, 5H),3.06-2.97(m, 1H), 3.37-3.30(m, 1H), 3.62(s, 3H), 3.78-3.71(m, 2H),4.03(s, 4H), 4.31-4.16(m, 2H), 4.43-4.32(m, 2H), 5.38-5.35(d, J=7.35 Hz,1H), 6.07-6.04(d, J=7.72 Hz, 1H), 6.43-6.40(d, J=9.19 Hz, 1H),6.69-6.66(d, J=8.46 Hz, 1H), 7.18-7.06(m, 5H), 7.23-7.20(d, J=8.46 Hz,2H), 7.37-7.26(m, 6H), 7.65-7.60(m, 1H), 7.95-7.92(d, J=8.46 Hz, 2H).

EXAMPLE 115methyl(1S)-1-[({(1S,3S,4S)-4-[((2S)-2-{3-[(6-tert-butyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}-3,3-dimethylbutanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 115A 2,2-dimethyl-5-hexen-3-ol

A solution of trimethylacetaldehyde (10.2 mL, 90.9 mmol) in diethylether (200 mL) at 0° C. was treated with allylmagnesium bromide (100 mL,1 M in ether), stirred at 0° C. for 1 hour, quenched with saturatedammonium chloride and extracted with diethyl ether. The organic phasewas washed with brine and dried over Na₂SO₄, filtered and concentratedto give the title compound (11.6 g).

EXAMPLE 115B ethyl5-(2-hydroxy-3,3-dimethylbutyl)-4,5-dihydro-3-isoxazolecarboxylate

A solution containing the product from Example 115A (7.83 g, 61.1 mmol)and ethyl chloroimidoacetate (20.4 g, 134.4 mmol) at 0° C. in diethylether (180 mL) was treated with a solution of triethylamine (24.7 mL,177.1 mmol) in diethyl ether (200 mL) over 2 hours, stirred at 0° C. for1 hour, filtered and concentrated. The concentrate was purified bychromatography on silica gel eluting with 10% ethyl acetate indichloromethane to give the title compound (6.76 g).

EXAMPLE 115C ethyl5-(3,3-dimethyl-2-oxobutyl)-4,5-dihydro-3-isoxazolecarboxylate

A solution of DMSO (3.94 mL, 55.6 mmol) in dichloromethane (90 mL) at−78° C. was treated dropwise with oxalyl chloride (20.8 mL, 2 M indichloromethane), stirred at −78° C. for 15 minutes, treated with asolution of the product from Example 115B (6.76 g, 27.8 mmol) indichloromethane (230 mL) over 10 minutes, stirred at −78° C. for 20minutes, treated dropwise with triethylamine (16.7 mL, 119.5 mmol) at−78° C., and after 10 minutes the reaction was warmed to 0° C., andstirred for an additional 10 minutes. The reaction mixture was quenchedwith water and partitioned between dichloromethane and water. Theorganic phase was washed with brine and dried over Na₂SO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with5% ethyl acetate in chloroform to give the title compound (4.9 g, 73%yield).

EXAMPLE 115D ethyl 6-tert-butyl-2-pyridinecarboxylate

A solution of the product from Example 115C (4.95 g, 20.5 mmol) inethanol (400 mL) was treated with Raney nickel (20.10 g) and 48% HBF₄solution (4.13 mL), and the reaction was shaken under a hydrogenatmosphere (50 psi) at 25° C. for 1 hour. The reaction mixture wasfiltered, diluted with water, basified with dilute NaOH solution, andpartitioned between dichloromethane and water. The organic phase waswashed with brine and dried over MgSO₄, filtered and concentrated. Theresidue was chromatographed on silica gel eluting with 10% ethyl acetatein hexane to give the title compound (1.1 g, 26% yield).

EXAMPLE 115E (6-tert-butyl-2-pyridinyl)methanol

A solution containing the product from Example 115D (1.1 g, 5.3 mmol) inTHF (20 mL) at −30° C. was treated with a solution of lithium aluminumhydride (5.3 mL, 1 M in THF), stirred at −30° C. for 5 minutes, treatedwith water (0.20 mL), 15% NaOH (0.20 mL), and water (0.40 mL)sequentially, stirred for 15 minutes at 25° C., filtered, rinsed withethyl acetate, and concentrated to give the title compound (0.88 g,quantitative).

EXAMPLE 115F 6-tert-butyl-2-pyridinecarbaldehyde

A solution of DMSO (0.90 mL, 12.7 mmol) in dichloromethane (10 mL) at−78° C. was treated with oxalyl chloride (3.1 mL, 2 M indichloromethane) dropwise, stirred for an additional 15 minutes at −78°C., treated with a solution of the product from Example 115E (0.88 g,5.3 mmol) in dichloromethane (14 mL) over 10 minutes, stirred for 20minutes, treated dropwise with triethylamine (3.6 mL, 26.1 mmol) at −78°C., stirred for 10 minutes, warmed to 0° C., stirred for an additional10 minutes, quenched with water and partitioned between dichloromethaneand water. The organic phase was washed with brine and dried overNa₂SO₄, filtered and concentrated. The residue was chromatographed onsilica gel eluting with 5% ethyl acetate in chloroform to give the titlecompound (0.77 g, 88% yield).

EXAMPLE 115Gtert-butyl(2S)-2-{3-[(6-tert-butyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}-3,3-dimethylbutanoate

A solution containing the product from Example 6F (1.14 g, 5.0 mmol) indichloromethane (12 mL) was treated with the product from Example 115F(0.77 mL, 4.7 mmol) and MgSO₄ (2.27 g, 18.9 mmol), stirred at 25° C. for16 hours, filtered and concentrated. A solution of the residue inmethanol (18 mL) was treated with sodium borohydride (0.27 g, 7.1 mmol),stirred at 25° C. for 1 hour, quenched with acetone (6 mL) andconcentrated. The concentrate was partitioned between ethyl acetate andsaturated NaHCO₃, and the organic phase was washed with brine and driedover Na₂SO₄, filtered and concentrated. A solution of the residue (4.7mmol) in 1,2-dichloroethane (18 mL) was treated with N,N-disuccinimidylcarbonate (1.45 g, 5.70 mmol) and triethylamine (0.66 mL, 4.70 mmol),stirred at 25° C. for 16 hours, and partitioned with 10% NaHCO₃. Theaqueous phase was extracted with additional dichloromethane. Thecombined organic phase was washed with brine, dried over Na₂SO₄,filtered and concentrated. The residue was chromatographed on silica geleluting with 2% methanol in chloroform to give the title compound (1.42g, 75% yield).

EXAMPLE 115H(2S)-2-{3-[(6-tert-butyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}-3,3-dimethylbutanoicacid

A solution containing the product from Example 115G (1.27 g, 3.15 mmol)in dichloromethane (6 mL) was treated with trifluoracetic acid (3 mL),stirred at 25° C. for 3 hours, and concentrated. The residue wasdissolved in ethyl acetate and concentrated several times to give thecrude product as the trifluoroacetic acid salt.

EXAMPLE 115Imethyl(1S)-1-[({(1S,3S,4S)-4-[((2S)-2-{3-[(6-tert-butyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}-3,3-dimethylbutanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 2C (0.035 g, 0.066 mmol)in THF (0.66 mL) was treated with the product from Example 115H (0.035g, 0.079 mmol), DEPBT (0.029 g, 0.098 mmol), andN,N-diisopropylethylamine (0.012 mL, 0.069 mmol), stirred at 25° C. for16 hours, and partitioned between chloroform and 10% Na₂CO₃ solution.The organic phase was washed with additional 10% Na₂CO₃ solution andbrine, dried over MgSO₄, filtered and concentrated. The residue waspurified by chromatography on silica gel eluting with 0-100% ethylacetate/dichloromethane, followed by 0-5% methanol in ethyl acetate togive the title compound (0.023 g, 40% yield). ¹H NMR (300 MHz, DMSO-d₆)δ ppm 0.83(s, 9H), 0.90(s, 9H), 1.31(s, 9H), 1.60-1.47(m, 2H),2.37-2.34(m, J=8.82 Hz, 1H), 2.61-2.53(m, 1H), 2.68-2.65(d, J=7.35 Hz,2H), 2.80-2.76(m, 1H), 3.03-2.98(m, 1H), 3.24-3.16(m, 1H), 3.50(s, 3H),3.70-3.60(m, 1H), 3.86-3.83(d, J=9.56 Hz, 1H), 4.08(s, 1H), 4.26-4.10(m,2H), 4.47-4.33(m, 2H), 4.55-4.52(d, J=7.72 Hz, 1H), 6.67-6.63(d, J=9.93Hz, 1H), 7.11-7.03(m, 6H), 7.23-7.21(d, J=8.09 Hz, 2H), 7.33-7.30(m,2H), 7.49-7.45(d, J=9.56 Hz, 1H), 7.75-7.69(t, J=7.72 Hz, 1H),7.91-7.82(m, 5H), 8.64-8.63(d, J=4.78 Hz, 1H).

EXAMPLE 116methyl(1S,4S,5S,7S,10S)-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-4,7-bis[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate

(i) A solution of the product from Example 112D (14 mg, 18 μmol) andthiocarbonyldiimidazole (10 mg, 56 μmol) in anhydrous THF (0.3 mL) wasstirred at 60° C. 3 days. The solvent was concentrated, and the crudeproduct was purified on by column chromatography on silica gel, elutingwith 50-80% ethyl acetate in hexanes (7.7 mg, 52%).

(ii) A solution of the product from step (i) in anhydrous toluene (0.2mL) was treated with tributyltin hydride (5 μL, 17 μmol) and2,2′-azobisisobutyronitrile (2 mg, 12 μmol). The resulting mixture washeated at reflux for 90 min, cooled to 25° C., and the crude product waspurified by column chromatography on silica gel, eluting with 50-100%ethyl acetate in hexanes (2.6 mg, 36%). ¹H NMR (300 MHz, CDCl₃) δ ppm0.89(m, 18H), 2.34(m, 2H), 2.88 (m, 4H), 3.62(s, 6H), 3.80(m, 2H),4.00(m, 1H), 4.18(m, 1H), 5.33(m, 2H), 6.08(m, 1H), 6.21(m, 1H), 7.31(m,2H), 7.72(m, 6H), 7.89(m, 4H), 8.67(m, 2H).

EXAMPLE 117methyl(1S)-1-[({(1R,3S,4S)-3-hydroxy-4-[((2S)-2-{3-[(6-isopropyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}-3,3-dimethylbutanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 117A tert-butyl(2S)-2-{3-[(6-acetyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}-3,3-dimethylbutanoate

A solution of the product from Example 17D (1.95 g, 4.815 mmol) intetrahydrofuran (50 mL) at −78° C. was treated methylmagnesium bromidein butyl ether (5.7 mL, 1 M). The mixture was stirred 0.5 hours at −78°C., quenched with acetone (3 mL) and 10% citric acid. The reactionmixture was partitioned between ethyl acetate and 1 N NaHCO₃, and theorganic phase layer was decanted and concentrated. The residue waspurified by flash chromatography on silica gel eluting with 25%-50%ethyl acetate in hexane give the title compound (1.6 g, 85% yield).

EXAMPLE 117B tert-butyl(2S)-2-{3-[(6-isopropenyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}-3,3-dimethylbutanoate

A solution of methyltriphenylphosphonium bromide (0.33 g, 0.923 mmol) inTHF (2.5 mL) was treated with a solution of potassium tert-butoxide inTHF (0.89 mL, 1 M) dropwise, stirred for 1 hour at 25° C., treated witha solution of the product from Example 117A (0.116 g, 0.298 mmol) in THF(2 mL), stirred at 25° C. for 16 hours, quenched with saturated ammoniumchloride solution and partitioned between ethyl acetate and water. Theorganic phase was washed with brine and dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with15%-25% ethyl acetate in hexane to give the title compound (0.040 g, 35%yield).

EXAMPLE 117C tert-butyl(2S)-2-{3-[(6-isopropyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}-3,3-dimethylbutanoate

A solution containing the product from Example 117B (0.038 g, 0.098mmol) in methanol (1 mL) was treated with 10% Pd on carbon (0.005 g) andthe reaction was stirred under an atmosphere of hydrogen (balloonpressure) for 2 hours. The reaction was filtered and the solvent wasconcentrated to give the title compound, which was used without furtherpurification.

EXAMPLE 117D(2S)-2-{3-[(6-isopropyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}-3,3-dimethylbutanoicacid

A solution of the product from Example 117C (0.098 mmol) indichloromethane (0.5 mL) was treated with trifluoroacetic acid (0.5 mL)and the mixture was stirred for 1 hour at 25° C. The solvent was removedunder reduced pressure and the residue was purified by reversed phasechromatography on a C18 column eluting with 5-100% acetonitrile in water(0.1% TFA) to give the title compound as the trifluroacetic acid salt(0.022 g, 52% yield).

EXAMPLE 117Emethyl(1S)-1-[({(1R,3S,4S)-3-hydroxy-4-[((2S)-2-{3-[(6-isopropyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}-3,3-dimethylbutanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 1H (0.025 g, 0.046 mmol)in THF (0.5 mL) was treated with the product from Example 117D (0.022 g,0.051 mmol), DEPBT (0.021 g, 0.070 mmol), and N,N-diisopropylethylamine(0.057 mL, 0.325 mmol), stirred at 25° C. for 16 hours, and partitionedbetween chloroform and 10% Na₂CO₃ solution. The organic phase was washedwith additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The product was purified by chromatography onsilica gel eluting with 0-100% ethyl acetate/dichloromethane, followedby 0-5% methanol in ethyl acetate to give the title compound (0.024 g,62% yield). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.80(s, 9H), 0.88(s, 9H),1.27-1.25(d, J=6.99 Hz, 6H), 1.42-1.23(m, 1H), 1.58-1.47(m, 1H),2.70-2.53(m, 3H), 2.87-2.78(m, 1H), 3.31-2.98(m, 4H), 3.57-3.50(m, 1H),3.57(s, 3H), 3.85-3.82(d, J=9.56 Hz, 1H), 3.99-3.87(m, 1H), 4.03(s, 1H),4.20-4.10, 4.23-4.13(m, 2H), 4.45(s, 2H), 6.91-6.87(d, J=9.93 Hz, 1H),7.10-7.06(m, 5H), 7.28-7.21(m, 4H), 7.44-7.37(m, 2H), 7.58-7.55(d,J=9.19 Hz, 1H), 7.97-7.86(m, 5H), 8.69-8.67(m, 1H).

EXAMPLE 118methyl(1S)-1-[({(1R,3S,4S)-4-[((2S)-2-{3-[(6-tert-butyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}-3,3-dimethylbutanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 1H (0.019 g, 0.036 mmol)in THF (0.43 mL) was treated with the product from Example 115H (0.019g, 0.043 mmol), DEPBT (0.016 g, 0.054 mmol), andN,N-diisopropylethylamine (0.063 mL, 0.360 mmol), stirred at 25° C. for16 hours, and partitioned between chloroform and 10% Na₂CO₃ solution.The organic phase was washed with additional 10% Na₂CO₃ solution andbrine, dried over MgSO₄, filtered and concentrated. The residue waspurified by chromatography on silica gel eluting with 0-100% ethylacetate/dichloromethane, followed by 0-5% methanol in ethyl acetate togive the title compound (0.012 g, 39% yield). ¹H NMR (300 MHz, DMSO-d6)δ ppm 0.80(s, 9H), 0.88(s, 9H), 1.30(s, 9H), 1.42-1.23(m, 1H),1.58-1.47(m, 1H), 2.47-2.42(m, 1H), 2.73-2.55(m, 2H), 2.87-2.78(m, 1H),3.05-2.99(m, 1H), 3.31-3.18(m, 1H), 3.57-3.50(m, 1H), 3.57(s, 3H),3.85-3.82(d, J=9.56 Hz, 1H), 3.99-3.87(m, 1H), 4.02(s, 1H), 4.23-4.13(m,1H), 4.44-4.32(m, 2H), 4.44-4.42(d, J=7.35 Hz, 1H), 6.90-6.87(d, J=9.19Hz, 1H), 7.09-7.04(m, 6H), 7.25-7.22(d, J=8.46 Hz, 2H), 7.34-7.29(m,2H), 7.54-7.51(d, J=9.91 Hz, 1H), 7.73-7.68(t, J=7.72 Hz, 1H),7.90-7.83(m, 3H), 7.97-7.94(d, J=8.09 Hz, 2H), 8.65-8.64(m, 1H).

EXAMPLE 119methyl(1S)-1-[({(1S,2S,4S)-4-{[(2S)-2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-2-hydroxy-1-[4-(6-methoxy-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 119A benzyl(4S,5S)-5-{(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}-4-[4-(6-methoxy-2-pyridinyl)benzyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate

A solution containing the product from Example 23I (0.20 g, 0.28 mmol)in DMF (3 mL) was treated with LiCl (0.119 g, 2.8 mmol),dichlorobis(triphenylphosphine)palladium(II) (0.060 g, 0.085 mmol), andthe product from Example 113A (0.338 g, 0.85 mmol), heated at 85° C. for64 hours, cooled and partitioned between ethyl acetate and water. Theorganic phase was washed with brine and dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with20% ethyl acetate in hexanes to give the title compound (0.097 g, 51%yield).

EXAMPLE 119B benzyl(1S,2S,4S)-4-amino-2-hydroxy-1-[4-(6-methoxy-2-pyridinyl)benzyl]-5-phenylpentylcarbamate

A solution containing the product from Example 119A (0.095 g, 0.14 mmol)in THF (1 mL) was treated with a solution of HCl in dioxane (0.25 mL, 4N), stirred at 50° C. for 16 hours, cooled and concentrated underreduced pressure. The residue was dissolved in ethanol and concentratedseveral times to give the title compound as hydrochloride salt, whichwas used without further purification.

EXAMPLE 119C benzyl(1S,2S,4S)-4-{[(2S)-2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-2-hydroxy-1-[4-(6-methoxy-2-pyridinyl)benzyl]-5-phenylpentylcarbamate

A solution containing the product from Example 119B (0.048 mmol) in THF(2 mL) was treated with the product from Example 70A (0.014 g, 0.048mmol), DEPBT (0.029 g, 0.095 mmol), and N,N-diisopropylethylamine (0.042mL, 0.235 mmol), stirred at 25° C. for 5 hours. The mixture waspartitioned between chloroform and 10% Na₂CO₃ solution. The organicphase was washed with additional 10% Na₂CO₃ solution and brine, driedover MgSO₄, filtered and concentrated. The residue was chromatographedon silica gel eluting with 2% methanol in chloroform to give the titlecompound (0.024 g, 62% yield).

EXAMPLE 119D(2S)—N-{(1S,3S,4S)-4-amino-1-benzyl-3-hydroxy-5-[4-(6-methoxy-2-pyridinyl)phenyl]pentyl}-2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanamide

A solution containing the product from Example 119C (0.024 g, 0.030mmol) in methanol (1 mL) was treated with 10% Pd on carbon (0.003 g) andHCl solution (0.030 mL, 4 N in dioxane), stirred under a hydrogenatmosphere (balloon pressure) at 25° C. for 16 hours, filtered through abed of celite and rinsed with methanol. The solvent was concentrated togive the crude product as a hydrochloride salt, which was used withoutfurther purification.

EXAMPLE 119Emethyl(1S)-1-[({(1S,2S,4S)-4-{[(2S)-2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-2-hydroxy-1-[4-(6-methoxy-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 119D (0.030 mmol) in THF(1 mL) was treated with the product from Example 1F (0.006 g, 0.033mmol), DEPBT (0.018 g, 0.059 mmol), and N,N-diisopropylethylamine (0.026mL, 0.148 mmol), stirred at 25° C. for 16 hours, and partitioned betweenchloroform and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was purified by chromatography on silica geleluting with 2% methanol in chloroform, to give the title compound. ¹HNMR (300 MHz, CDCl₃) δ ppm 0.96(s, 9H), 1.00(s, 9H), 1.67-1.55(m, 2H),2.67-2.60(m, 1H), 2.96-2.73m, 5H), 3.08-2.99q, J=8.46 Hz, 1H),3.43-3.36(m, 1H), 3.62(bs, 4H), 3.82-3.79(d, J=8.82 Hz, 1H), 4.00(s,1H), 4.04(s, 3H), 4.16-4.09(m, 2H), 4.45-4.25(m, 2H), 5.34-5.27(m, 1H),6.12-6.09(m, 2H), 6.69-6.66(d, J=8.09 Hz, 1H), 7.15-7.06(m, 6H),7.36-7.23(m, 7H), 7.65-7.59(m, 1H), 7.95-7.92(d, J=8.09 Hz, 2H).

EXAMPLE 120methyl(1S,4S,5S,7S,10S)-7-benzyl-1,10-ditert-butyl-5-hydroxy-4-[4-(6-methoxy-2-pyridinyl)benzyl]-2,9,12-trioxo-13-oxa-3,8,11-triazatetradec-1-ylcarbamateEXAMPLE 120Abenzyl(1S,2S,4S)-2-hydroxy-4-({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-1-[4-(6-methoxy-2-pyridinyl)benzyl]-5-phenylpentylcarbamate

A solution containing the product from Example 119B (0.048 mmol) in THF(2 mL) was treated with the product from Example 1F (0.009 g, 0.048mmol), DEPBT (0.029 g, 0.095 mmol), and N,N-diisopropylethylamine (0.042mL, 0.235 mmol), stirred at 25° C. for 5 hours, and partitioned betweenchloroform and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with2% methanol in chloroform to give the title compound (0.028 g, 85%yield).

EXAMPLE 120Bmethyl(1S)-1-[({(1S,3S,4S)-4-amino-1-benzyl-3-hydroxy-5-[4-(6-methoxy-2-pyridinyl)phenyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 120A (0.028 g, 0.041mmol) in methanol (1 mL) was treated with 10% Pd on carbon (0.003 g) andHCl solution (0.030 mL, 4 N in dioxane), and the reaction was stirredunder a hydrogen atmosphere (balloon pressure) at 25° C. for 16 hours.The reaction was filtered through a bed of celite and rinsed withmethanol. The solvent was concentrated to give the title compound as thehydrochloride salt, which was used without further purification.

EXAMPLE 120Cmethyl(1S,4S,5S,7S,10S)-7-benzyl-1,10-ditert-butyl-5-hydroxy-4-[4-(6-methoxy-2-pyridinyl)benzyl]-2,9,12-trioxo-13-oxa-3,8,11-triazatetradec-1-ylcarbamate

A solution containing the product from Example 120B (0.041 mmol) in THF(1 mL) was treated with the product from Example 1F (0.009 g, 0.045mmol), DEPBT (0.024 g, 0.082 mmol), and N,N-diisopropylethylamine (0.036mL, 0.204 mmol) and the mixture was stirred at 25° C. for 16 hours. Themixture was partitioned between chloroform and 10% Na₂CO₃ solution. Theorganic phase was washed with additional 10% Na₂CO₃ solution and brine,dried over MgSO₄, filtered and concentrated. The residue was purified bychromatography on silica gel eluting with 2% methanol in chloroform, togive the title compound. ¹H NMR (300 MHz, CDCl₃) δ ppm 0.91(s, 9H),0.94(s, 9H), 1.67-1.54(m, 2H), 2.80-2.74(m, 2H), 2.89-2.87(d, J=7.35 Hz,2H), 3.62(s, 3H), 3.67(s, 3H), 3.74-3.61(m, 2H), 3.82-3.79(d, J=9.19 Hz,1H), 4.00-3.93(m, 1H), 4.04(s, 3H), 4.13-4.04(m, 1H), 5.32-5.28(m, 2H),5.96-5.94(d, J=6.99 Hz, 1H), 6.14-6.11(d, J=8.82 Hz, 1H), 6.69-6.67(d,J=7.72 Hz, 1H), 7.08-7.06(d, J=6.62 Hz, 2H), 7.33-7.15(m, 6H),7.66-7.60(m, 1H), 7.95-7.92(d, J=8.09 Hz, 2H).

EXAMPLE 121methyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-ditert-butyl-5-hydroxy-7-[4-(6-methoxy-2-pyridinyl)benzyl]-2,9,12-trioxo-13-oxa-3,8,11-triazatetradec-1-ylcarbamate

A solution of the product from Example 113C (0.074 g, 0.12 mmol) in THF(2 mL) was treated with an HCl solution (0.21 mL, 4 N in dioxane), andthe reaction was stirred at 50° C. for 16 hours. The solvent was removedunder reduced pressure and ethanol added and concentrated several times.A solution of the concentrate (0.12 mmol) in methanol (2 mL) was treatedwith Pd on carbon (0.007 g, 10% Pd by wt.), and the reaction was stirredunder a hydrogen atmosphere (balloon pressure) at 25° C. for 16 hours.The reaction mixture was filtered through a bed of celite®, rinsed withmethanol, and concentrated. A solution of the concentrate (0.12 mmol) inTHF (0.5 mL) was treated with the product from Example 1F (0.047 g, 0.25mmol), DEPBT (0.142 g, 0.47 mmol), and N,N-diisopropylethylamine (0.207mL, 1.19 mmol), stirred at 25° C. for 16 hours, and partitioned betweenchloroform and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with1.5% methanol in chloroform, to give the title compound. ¹H NMR (300MHz, CDCl₃) δ ppm 0.93(s, 18H), 1.65-1.58(m, 2H), 2.90-2.74(m, 4H),3.63(s, 3H), 3.68(s, 3H), 3.80-3.63(m, 3H), 3.98-3.92(m, 1H), 4.04(s,3H), 4.20-4.11(m, 1H), 5.32-5.35(m, 2H), 6.02-6.00(d, J=8.09 Hz, 1H),6.11-6.08(d, J=8.82 Hz, 1H), 6.69-6.67(d, J=7.72 Hz, 1H), 7.33-7.14(m,8H), 7.65-7.60(m, 1H), 7.94-7.91(d, J=8.09 Hz, 2H).

EXAMPLE 122methyl(1S)-1-[({(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-1-[4-(6-methoxy-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 122Abenzyl(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-1-[4-(6-methoxy-2-pyridinyl)benzyl]-5-phenylpentylcarbamate

A solution containing the product from Example 119B (0.048 mmol) in THF(2 mL) was treated with the product from Example 10D (0.016 g, 0.048mmol), DEPBT (0.029 g, 0.095 mmol), and N,N-diisopropylethylamine (0.042mL, 0.235 mmol), stirred at 25° C. for 5 hours, and partitioned betweenchloroform and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with2% methanol in chloroform to give the title compound (0.018 g, 47%yield).

EXAMPLE 122B(2S)-N-{(1S,3S,4S)-4-amino-1-benzyl-3-hydroxy-5-[4-(6-methoxy-2-pyridinyl)phenyl]pentyl}-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanamide

A solution containing the product from Example 122A (0.018 g, 0.022mmol) in methanol (1 mL) was treated with 10% Pd on carbon (0.002 g) andHCl solution (0.030 mL, 4 N in dioxane), stirred under a hydrogenatmosphere (balloon pressure) at 25° C. for 16 hours, filtered through abed of celite and rinsed with methanol. The solvent was concentrated togive the crude product as the hydrochloride salt, which was used withoutfurther purification.

EXAMPLE 122Cmethyl(1S)-1-[({(1S,2S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-2-hydroxy-1-[4-(6-methoxy-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 122B (0.022 mmol) in THF(1 mL) was treated with the product from Example 1F (0.005 g, 0.024mmol), DEPBT (0.013 g, 0.044 mmol), and N,N-diisopropylethylamine (0.020mL, 0.111 mmol), stirred at 25° C. for 16 hours, and partitioned betweenchloroform and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was purified by chromatography on silica geleluting with 2% methanol in chloroform, to give the title compound. ¹HNMR (300 MHz, CDCl₃) δ ppm 0.96(s, 9H), 1.01(s, 9H), 1.67-1.59(m, 2H),2.55(s, 3H), 2.67-2.59(m, 1H), 2.84-2.73(m, 2H), 2.91-2.89(d, J=7.72 Hz,2H), 3.10-3.02(m, 1H), 3.23-3.14(q, J=8.95 Hz, 1H), 3.46-3.39(m, 1H),3.68-3.62(m, 1H), 3.62(s, 3H), 3.82-3.79(d, J=9.19 Hz, 1H), 3.99(s, 1H),4.04(s, 3H), 4.17-4.07(m, 2H), 4.59-4.34(m, 2H), 5.32-5.29(d, J=8.46 Hz,1H), 6.12-6.09(d, J=9.19 Hz, 1H), 6.21-6.11(m, 1H), 6.68-6.66(d, J=7.72Hz, 1H), 7.14-7.01(m, 7H), 7.33-7.27(m, 3H), 7.58-7.53(t, J=7.72 Hz,1H), 7.64-7.61(m, 1H), 7.95-7.93(d, J=8.46 Hz, 2H).

EXAMPLE 123methyl(1S)-1-[({(1S,3S,4S)-4-({(2S)-2-[3-(2-aminobenzyl)-2-oxo-1-imidazolidinyl]-3,3-dimethylbutanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 123A(2S)-3,3-dimethyl-2-[3-(2-nitrobenzyl)-2-oxo-1-imidazolidinyl]butanoicacid

A solution containing the product from Example 6F (0.162 g, 0.702 mmol)in a mixture of benzene (3.5 mL) and methanol (3.5 mL) was treated with2-nitrobenzaldehyde (0.112 mL, 0.737 mmol), stirred at 50° C. for 16hours, cooled to 25° C., treated with sodium borohydride (0.053 g, 1.4mmol), stirred at 25° C. for 2 hours, quenched with saturated NaHCO₃,and partitioned between ethyl acetate and saturated NaHCO₃. The organicphase was washed with brine and dried over MgSO₄, filtered andconcentrated. A solution of the concentrate (0.702 mmol) in1,2-dichloroethane (7 mL) was treated with N,N-disuccinimidyl carbonate(0.216 g, 0.842 mmol) and triethylamine (0.117 mL, 0.842 mmol), stirredat 25° C. for 16 hours, diluted with dichloromethane and partitionedwith 10% Na₂CO₃. The organic phase was washed with brine, dried overMgSO₄, filtered and concentrated. A solution of the concentrate (0.702mmol) in dichloromethane (3.5 mL) was treated with trifluoracetic acid(3.5 mL), stirred at 25° C. for 2 hours and concentrated. The residuewas purified by reversed phase chromatography on a C18 column elutingwith a gradient starting with 5-100% acetonitrile in water (0.1% TFA),to give the title compound (0.12 g, 50% yield).

EXAMPLE 123Bmethyl(1S)-1-[({(1S,3S,4S)-4-({(2S)-3,3-dimethyl-2-[3-(2-nitrobenzyl)-2-oxo-1-imidazolidinyl]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 2C (0.082 g, 0.154 mmol)in THF (1.5 mL) was treated with the product from Example 123A (0.057 g,0.17 mmol), DEPBT (0.069 g, 0.231 mmol), and N,N-diisopropylethylamine(0.135 mL, 0.77 mmol), stirred at 25° C. for 16 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was chromatographed on silica geleluting with 0-100% acetate/dichloromethane, followed by 0-5% methanolin ethyl acetate to give the title compound (0.080 g, 61% yield).

EXAMPLE 123Cmethyl(1S)-1-[({(1S,3S,4S)-4-({(2S)-2-[3-(2-aminobenzyl)-2-oxo-1-imidazolidinyl]-3,3-dimethylbutanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 123B (0.027 g, 0.031mmol) in ethanol (1 mL) was treated with 10% Pd on carbon (0.010 g),stirred under an atmosphere of hydrogen (balloon pressure) at 25° C. for2.5 hours, filtered and concentrated under reduced pressure. The residuewas purified by reversed phase chromatography on a C18 column elutingwith 5-100% acetonitrile in water (0.1% TFA). The product waspartitioned between ethyl acetate and saturated NaHCO₃, and the organicphase was washed with brine and dried over MgSO₄, filtered andconcentrated to give the title compound (0.014 g, 55% yield). ¹H NMR(300 MHz, DMSO-d₆) δ ppm 0.84(s, 9H), 0.86(s, 9H), 1.63-1.46(m, 2H),2.16-2.07(m, 1H), 2.65-2.54(m, 3H), 3.00-2.74(m, 3H), 3.18-3.08(m, 1H),3.50(s, 3H), 3.71-3.62(m, 1H), 3.87-3.83(d, J=9.56 Hz, 1H), 4.05(s, 1H),4.28-4.10(m, 4H), 4.53-4.51(d, J=7.72 Hz, 1H), 5.20(s, 2H), 6.56-6.51(t,J=7.35 Hz, 1H), 6.68-6.64(m, 2H), 7.08-6.92(m, 7H), 7.24-7.21(d, J=8.09Hz, 2H), 7.33-7.29(m, 1H), 7.43-7.40(d, J=9.93 Hz, 1H), 7.91-7.82(m,5H), 8.64-8.63(d, J=4.41 Hz, 1H).

EXAMPLE 124methyl(1S)-1-[({(1S,3S,4S)-4-({(2S)-2-[3-(4-aminobenzyl)-2-oxo-1-imidazolidinyl]-3,3-dimethylbutanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 124A(2S)-3,3-dimethyl-2-[3-(4-nitrobenzyl)-2-oxo-1-imidazolidinyl]butanoicacid

A solution containing the product from Example 6F (0.161 g, 0.700 mmol)in a mixture of benzene (3.5 mL) and methanol (3.5 mL) was treated with4-nitrobenzaldehyde (0.111 mL, 0.735 mmol), stirred at 50° C. for 16hours, cooled to 25° C., treated with sodium borohydride (0.053 g, 1.4mmol), stirred at 25° C. for 2 hours, quenched with saturated NaHCO₃,and partitioned between ethyl acetate and saturated NaHCO₃. The organicphase was washed with brine and dried over MgSO₄, filtered andconcentrated. A solution of the concentrate (0.700 mmol) in1,2-dichloroethane (7 mL) was treated with N,N-disuccinimidyl carbonate(0.215 g, 0.839 mmol) and triethylamine (0.117 mL, 0.842 mmol), stirredat 25° C. for 16 hours, diluted with dichloromethane and partitionedwith 10% Na₂CO₃. The organic phase was washed with brine, dried overMgSO₄, filtered and concentrated. A solution containing of theconcentrate (0.700 mmol) in dichloromethane (3 mL) was treated withtrifluoracetic acid (3 mL), and the mixture was stirred at 25° C. for 2hours. The solvent was concentrated, and the residue was purified byreversed phase chromatography on a C18 column eluting with a gradientstarting with 5-100% acetonitrile in water (0.1 % TFA), to give thetitle compound (0.17 g, 62% yield).

EXAMPLE 124Bmethyl(1S)-1-[({(1S,3S,4S)-4-({(2S)-3,3-dimethyl-2-[3-(4-nitrobenzyl)-2-oxo-1-imidazolidinyl]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 2C (0.074 g, 0.138 mmol)in THF (1.5 mL) was treated with the product from Example 124A (0.051 g,0.152 mmol), DEPBT (0.062 g, 0.207 mmol), and N,N-diisopropylethylamine(0.120 mL, 0.691 mmol), stirred at 25° C. for 16 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was chromatographed on silica geleluting with 0-100% ethyl acetate/dichloromethane, followed by 0-5%methanol in ethyl acetate to give the title compound (0.066 g, 56%yield).

EXAMPLE 124Cmethyl(1S)-1-[({(1S,3S,4S)-4-({(2S)-2-[3-(4-aminobenzyl)-2-oxo-1-imidazolidinyl]-3,3-dimethylbutanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 124B (0.065 g, 0.076mmol) in ethanol (1.5 mL) was treated with 10% Pd on carbon (0.024 g),stirred under an atmosphere of hydrogen (balloon pressure) at 25° C. for2.5 hours, filtered concentrated under reduced pressure. The residue waspurified by reversed phase chromatography on a C18 column eluting with agradient starting with 5-100% acetonitrile in water (0.1% TFA). Theproduct was partitioned between ethyl acetate and saturated NaHCO₃, andthe organic phase was washed with brine and dried over MgSO₄, filteredand concentrated to give the title compound (0.024 g, 39% yield). ¹H NMR(300 MHz, DMSO-d₆) δ ppm 0.83(s, 9H), 0.87(s, 9H), 1.60-1.48(m, 2H),2.29-2.20(m, 1H), 2.67-2.53(m, 3H), 2.92-2.75(m, 3H), 3.16-3.08(m, 1H),3.50(s, 3H), 3.71-3.61(m, 1H), 3.86-3.83(d, J=9.93 Hz, 1H), 4.07(s, 1H),4.11(s, 2H), 4.23-4.09(m, 2H), 4.56-4.53(d, J=7.72 Hz, 1H), 5.00(s, 2H),6.55-6.52(d, J=8.46 Hz, 2H), 6.67-6.64(d, J=9.93 Hz, 1H), 6.94-6.91(d,J=8.46 Hz, 2H), 7.10-7.02(m, 5H), 7.23-7.21(d, J=8.46 Hz, 2H),7.33-7.29(m, 1H), 7.45-7.42(d, J=9.56 Hz, 1H), 7.91-7.82(m, 5H),8.64-8.62(m, 1H).

EXAMPLE 125methyl(1S)-1-[({(1S,3S,4S)-4-({(2S)-2-[3-(3-aminobenzyl)-2-oxo-1-imidazolidinyl]-3,3-dimethylbutanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 125Atert-butyl(2S)-3,3-dimethyl-2-[3-(3-nitrobenzyl)-2-oxo-1-imidazolidinyl]butanoate

A solution containing the product from Example 6F (0.215 g, 0.933 mmol)in a mixture of benzene (3 mL) and methanol (3 mL) was treated with3-nitrobenzaldehyde (0.148 mL, 0.98 mmol), and the mixture was stirredat 50° C. for 16 hours, cooled to 25° C., treated with sodiumborohydride (0.071 g, 1.88 mmol), stirred at 25° C. for 2 hours,quenched with saturated NaHCO₃, and partitioned between ethyl acetateand saturated NaHCO₃. The organic phase was washed with brine and driedover MgSO₄, filtered and concentrated. A solution of the concentrate(0.933 mmol) in 1,2-dichloroethane (9 mL) was treated withN,N-disuccinimidyl carbonate (0.287 g, 1.12 mmol) and triethylamine(0.156 mL, 1.12 mmol), stirred at 25° C. for 16 hours, diluted withdichloromethane and partitioned with 10% Na₂CO₃. The organic phase waswashed with brine, dried over MgSO₄, filtered and concentrated. Theresidue was chromatographed on silica gel eluting with 0-25% ethylacetate in hexane to give the title compound (0.209 g, 56% yield).

EXAMPLE 125B(2S)-3,3-dimethyl-2-[3-(3-nitrobenzyl)-2-oxo-1-imidazolidinyl]butanoicacid

A solution containing the product from Example 125B (0.209 g, 0.53 mmol)in dichloromethane (2.5 mL) was treated with trifluoracetic acid (2.5mL), and the mixture was stirred at 25° C. for 1 hour. The solvent wasconcentrated and the residue was dissolved in ethyl acetate andconcentrated several times to give the crude product, which was usedwithout further purification.

EXAMPLE 125Cmethyl(1S)-1-[({(1S,3S,4S)-4-({(2S)-3,3-dimethyl-2-[3-(3-nitrobenzyl)-2-oxo-1-imidazolidinyl]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 2C (0.065 g, 0.123 mmol)in THF (1 mL) was treated with the product from Example 125B (0.049 g,0.147 mmol), DEPBT (0.055 g, 0.185 mmol), and N,N-diisopropylethylamine(0.102 mL, 0.615 mmol), stirred at 25° C. for 16 hours, and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic phase waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was chromatographed on silica geleluting with 0-100% ethyl acetate/dichloromethane, followed by 0-5%methanol in ethyl acetate to give the title compound (0.077 g, 74%yield).

EXAMPLE 125Dmethyl(1S)-1-[({(1S,3S,4S)-4-({(2S)-2-[3-(3-aminobenzyl)-2-oxo-1-imidazolidinyl]-3,3-dimethylbutanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 125C (0.077 g, 0.091mmol) in ethanol (2 mL) was treated with 10% Pd on carbon (0.029 g),stirred under an atmosphere of hydrogen (balloon pressure) at 25° C. for3 hours, filtered and concentrated under reduced pressure. The residuewas purified by reversed phase chromatography on a C18 column elutingwith 5-100% acetonitrile in water (0.1% TFA. The product was partitionedbetween ethyl acetate and saturated NaHCO₃, and the organic phase waswashed with brine and dried over MgSO₄, filtered and concentrated togive the title compound (0.035 g, 47% yield). ¹H NMR (300 MHz, DMSO-d₆)δ ppm 0.83(s, 9H), 0.89(s, 9H), 1.60-1.49(m, 2H), 2.38-2.28(m, 1H),2.62-2.53(m, 1H), 2.68-2.66(m, 2H), 2.86-2.76(m, 2H), 2.98-2.89(q,J=9.19 Hz, 1H), 3.20-3.14(m, 1H), 3.50(s, 3H), 3.70-3.62(m, 1H),3.86-3.83(d, J=9.93 Hz, 1H), 4.07(s, 1H), 4.14(s, 2H), 4.25-4.10(m, 2H),4.55-4.53(d, J=7.35 Hz, 1H), 5.03(s, 2H), 6.42-6.39(d, J=7.35 Hz, 1H),6.48-6.66(m, 2H), 6.62-6.59(d, J=9.93 Hz, 1H), 7.01-6.96(t, J=7.91 Hz,1H), 7.11-7.04(m, 5H), 7.24-7.21(d, J=8.09 Hz, 2H), 7.33-7.28(m, 1H),7.40-7.37(d, J=9.19 Hz, 1H), 7.91-7.80(m, 5H), 8.64-8.63(d, J=4.41 Hz,1H).

EXAMPLE 126tert-butyl(1S,3S,4S)-4-amino-1-benzyl-3-hydroxy-5-phenylpentylcarbamate,Succinate Salt

The title compound was prepared from L-phenylalanine using theprocedures as described in U.S. Pat. No. 5,914,332, Examples 1A to 1F-2.

EXAMPLE 127 (2S,3S,5S)-2,5-diamino-1,6-diphenyl-3-hexanol

The title compound was prepared from Cbz-L-phenylalaninol using theprocedures as described in Kempf, D. J.; Marsh K. C.; Codacovi Fino, L.;Bryant, P.; Craig-Kennard, A.; Sham, H. L.; Zhao, C.; Vasavanonda, S.;Kohlbrenner, W. E.; Wideburg, N. E.; Saldivar, A.; Green, B. E.; Herrin,T.; Norbeck, D. W. Bioorganic and Medicinal Chemistry 1994, 2, 847-858,and in Kempf, D. J.; Sowin, T. J.; Doherty, E. M.; Hannick, S. M.;Codavoci, L.; Henry, R. F.; Green, B. E.; Spanton, S. G.; Norbeck, D. W.Journal of Organic Chemistry 1992, 57, 5692-5700.

EXAMPLE 128methyl(1S)-1-[({(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-1-[4-(5-methyl-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 128Abenzyl(3S,4S)-1-(4-bromobenzyl)-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-5-phenylpentylcarbamate

A solution of a mixture of the products from Examples 92D and Example92E (prior to separation by chromatography) (2.4 g, 3.37 mmol) wastreated with TBAF solution in THF (19 mL, 1N), stirred at 25° C. for 16hours, concentrated, and partitioned between ethyl acetate and water.The organic was washed with brine, dried over MgSO₄, filtered andconcentrated to give the product, which was used without furtherpurification.

EXAMPLE 128B tert-butyl(4S,5S)-4-benzyl-5-[2-{[(benzyloxy)carbonyl]amino}-3-(4-bromophenyl)propyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate

A solution containing the product from Example 128A (3.37 mmol) in2,2-dimethoxypropane (35 mL) was treated with p-toluenesulfonic acidmonohydrate (0.032 g, 0.17 mmol), stirred at 25° C. for 1 hour, treatedwith triethylamine (0.14 mL, 1.0 mmol), and the reaction was partitionedbetween ethyl acetate and water. The organic phase was washed withbrine, dried over MgSO₄, filtered and concentrated to give the product(1.16 g, 54% yield), which was used without further purification.

EXAMPLE 128Ctert-butyl(4S,5S)-4-benzyl-5-{2-{[(benzyloxy)carbonyl]amino}-3-[4-(5-methyl-2-pyridinyl)phenyl]propyl}-2,2-dimethyl-1,3-oxazolidine-3-carboxylate

A solution containing the product from Example 128B (0.50 g, 0.78 mmol)in DMF (8 mL) was treated withdichlorobis(triphenylphosphine)palladium(II) (0.165 g, 0.235 mmol), andthe product from Example 74A (0.60 g, 1.63 mmol), stirred at 100° C. for6 hours, cooled to 25° C., filtered through celite®, and partitionedbetween ethyl acetate and water. The organic was washed with brine,dried over MgSO₄, filtered and concentrated. The residue waschromatographed on silica gel eluting with 0-15% ethyl acetate inchloroform to give the product (0.322 g, 63% yield).

EXAMPLE 128Dbenzyl(3S,4S)-4-amino-3-hydroxy-1-[4-(5-methyl-2-pyridinyl)benzyl]-5-phenylpentylcarbamate

A solution containing the product from Example 128C (0.322 g, 0.496mmol) in a mixture of THF (5 mL), methanol (5 mL), and aqueous HCl (5mL, 1 N) was stirred at 60° C. for 16 hours. The solvent was removedunder reduced pressure to give the title compound as the hydrochloridesalt.

EXAMPLE 128Ebenzyl(3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1imidazolidinyl}butanoyl)amino]-3-hydroxy-1-[4-(5-methyl-2-pyridinyl)benzyl]-5-phenylpentylcarbamate

A solution containing the product from Example 128D (0.496 mmol) in THF(5 mL) was treated with the product from Example 10D (0.205 g, 0.600mmol), DEPBT (0.225 g, 0.753 mmol), and N,N-diisopropylethylamine (0.875mL, 5.02 mmol), stirred at 25° C. for 3 hours, and partitioned betweenethyl acetate and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and then brine, dried over MgSO₄,filtered and concentrated. The residue was chromatographed on silica geleluting with 0-100% ethyl acetate/dichloromethane, followed by 50%methanol in ethyl acetate to give the product (0.127 g, 32% yield).

EXAMPLE 128F(2S)-N-{(1S,2S)-4-amino-1-benzyl-2-hydroxy-5-[4-(5-methyl-2-pyridinyl)phenyl]pentyl}-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanamide

A solution containing the product from Example 128E (0.127 g, 0.159mmol) in methanol (2 mL) was treated with Pd(OH)₂ on carbon (0.035 g,20% Pd by wt.) and HCl solution (0.12 mL, 4N in dioxane), stirred undera hydrogen atmosphere (balloon pressure) at 25° C. for 16 hours,filtered through a bed of celite® and rinsed with methanol. The solventwas concentrated to give the title compound as the hydrochloride salt,which was used without further purification.

EXAMPLE 128Gmethyl(1S)-1-[({(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-1-[4-(5-methyl-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 128F (0.159 mmol) in THF(1.6 mL) was treated with the product from Example 1F (0.036 g, 0.190mmol), DEPBT (0.075 g, 0.251 mmol), and N,N-diisopropylethylamine (0.30mL, 1.72 mmol), stirred at 25° C. for 16 hours, and partitioned betweenethyl acetate and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The product was purified by chromatography on silica geleluting with 0-50% acetone in dichloromethane, to give the lower Rf (50%acetone in dichloromethane) product of the mixture (0.01 g). ¹H NMR (300MHz, DMSO-d₆), δ ppm 0.83 (s, 9 H), 0.90 (s, 9 H), 1.55 (m, 2 H), 2.32(s, 3H), 2.38 (q, J=9.2 Hz, 1 H), 2.46 (s, 3 H), 2.57 (m, 1 H), 2.67 (d,J=7.0 Hz, 2 H), 2.79 (m, 1 H), 2.97 (m, 1 H), 3.09 (q, J=8.95 Hz, 1 H),3.21 (m, 1 H), 3.51 (s, 3 H), 3.67 (m, 1 H), 3.85 (d, J=9.6 Hz, 1 H),4.08 (s, 1H), 4.12 (m, 3 H), 4.35 (m, 2 H), 4.54 (d, J=7.35 Hz, 1 H),6.63 (d, J=9.56 Hz, 1 H), 7.09 (m, 5 H), 7.14 (d, J=7.7 Hz, 1 H), 7.18(d, J=8.6 Hz, 2 H), 7.48 (d, J=9.56 Hz, 1 H), 7.66 (m, 1H), 7.68 (t,J=7.7 Hz, 1 H), 7.86 (m, 4 H), 8.46 (br s, 1 H).

EXAMPLE 129methyl(1S)-1-[({(1R,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-1-[4-(5-methyl-2-pyridinyl)benzyl]-5-phenylpentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 128F (0.159 mmol) in THF(1.6 mL) was treated with the product from Example IF (0.036 g, 0.190mmol), DEPBT (0.075 g, 0.251 mmol), and N,N-diisopropylethylamine (0.30mL, 1.72 mmol), stirred at 25° C. for 16 hours, and partitioned betweenethyl acetate and 10% Na₂CO₃ solution. The organic was washed withadditional 10% Na₂CO₃ solution and then brine, dried over MgSO₄,filtered and concentrated. The residue was purified by chromatography onsilica gel eluting with 0-50% acetone in dichloromethane, to give thehigher Rf (50% acetone in dichloromethane) product of the mixture (0.01g). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.80 (s, 9 H), 0.88 (s, 9 H), 1.37(m, 1 H), 1.52 (m, 1 H), 2.32 (s, 3H), 2.45 (s, 3 H), 2.66 (m, 3 H),2.83 (dd, J=13.79, 6.07 Hz, 1 H), 3.03 (m, 2 H), 3.23 (m, 1 H), 3.53 (m,4 H), 3.83 (d, J=9.56 Hz, 1 H), 4.01 (m, 2 H), 4.03 (s, 1H), 4.16 (m, 1H), 4.33 (m, 2 H), 4.43 (d, J=6.99 Hz, 1 H), 6.88 (d, J=9.56 Hz, 1 H),7.09 (m, 5 H), 7.14 (d, J=7.35 Hz, 1 H ), 7.21 (d, J=8.09 Hz, 2 H), 7.54(d, J=9.56 Hz, 1 H), 7.67 (m, 2 H), 7.81 (m, 2 H), 7.93 (d, J=8.45 Hz,2H), 8.48 (br s, 1 H).

EXAMPLE 130 tert-butyl2-({(1S)-1-[({(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropyl}amino)-2-oxoethylcarbamateEXAMPLE 130Abenzyl(1S,3S,4S)-4-amino-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentylcarbamate

A solution containing the product from Example 1C (0.088 g, 0.15 mmol)in a mixture of THF (2 mL) and aqueous HCl (0.26 mL, 4 N) was stirred at25° C. for 16 hours, then heated at 60° C. for 2 hours, cooled andconcentrated. The residue was treated with ethanol and concentratedseveral times to give the title compound as the hydrochloride salt,which was used without further purification.

EXAMPLE 130Bbenzyl(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentylcarbamate

A solution containing the product from Example 130A (0.15 mmol) in DMF(1 mL) was treated with the product from Example 10D (0.045 g, 0.15mmol), EDAC (0.072 g, 0.375 mmol), HOBT (0.051 g, 0.375 mmol), and NMM(0.222 mL, 2.02 mmol), stirred at 25° C. for 40 hours, and partitionedbetween ethyl acetate and water. The organic was washed with brine,dried over Na₂SO₄, filtered and concentrated. The residue was purifiedby chromatography on silica gel eluting with 1-5% methanol inchloroform, to give the product (0.067 g, 58% yield).

EXAMPLE 130C(2S)—N-{(1S,2S,4S)-4-amino-1-benzyl-2-hydroxy-5-[4-(2-pyridinyl)phenyl]pentyl}-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanamide

A solution containing the product from Example 130B (0.067 g, 0.086mmol) in methanol (3 mL) was treated with a solution of HCl in dioxane(0.025 mL, 4 M) and Pd on carbon (0.007 g, 10% Pd by wt.), stirred undera hydrogen atmosphere (balloon pressure) at 25° C. for 16 hours,filtered through a bed of celite® and rinsed with methanol. The solventwas concentrated to give the title compound as the hydrochloride salt(0.053 g), which was used without further purification.

EXAMPLE 130Dtert-butyl(1S)-1-[({(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 130C (0.053 g, 0.081mmol) in DMF (1 mL) was treated with Boc-L-tert-leucine (0.019 g, 0.081mmol), EDAC (0.023 g, 0.122 mmol), HOBT (0.016 g, 0.122 mmol), and NMM(0.018 mL, 0.162 mmol), stirred at 25° C. for 40 hours, and partitionedbetween ethyl acetate and water. The organic phase was washed withbrine, and then dried over MgSO₄, filtered and concentrated. The residuewas purified by chromatography on silica gel eluting with 20% ethylacetate in chloroform, to give the product (0.024 g, 34% yield).

EXAMPLE 130E(2S)-2-amino-N-{(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}-3,3-dimethylbutanamide

A solution containing the product from Example 130D (0.024 g, 0.028mmol) in a mixture of THF (1 mL) and aqueous HCl (0.050 mL, 4 N) wasstirred at 25° C. for 16 hours, and concentrated under reduced pressure.The residue was treated with ethanol and concentrated several times togive the title compound as the hydrochloride salt, which was usedwithout further purification.

EXAMPLE 130F tert-butyl2-({(1S)-1-[({(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropyl}amino)-2-oxoethylcarbamate

A solution containing the product from Example 130E (0.028 mmol) in DMF(1 mL) were added Boc-glycine (0.005 g, 0.028 mmol), EDAC (0.008 g,0.042 mmol), HOBT (0.0056 g, 0.042 mmol), and NMM (0.018 mL, 0.162mmol), stirred at 25° C. for 40 hours, and partitioned between ethylacetate and water. The organic phase was washed with brine, dried overMgSO₄, filtered and concentrated. The residue was purified bychromatography on silica gel eluting with 2% methanol in chloroform, togive the product. ES-MS: m/z 920 [M+H]⁺.

EXAMPLE 131methyl(1S)-1-[({(1S,3S,4S)-3-hydroxy-4-[((2S)-2-{3-[(6-isopropyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}-3,3-dimethylbutanoyl)amino]-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 2C (0.025 g, 0.066 mmol)in THF (0.66 mL) was treated with the product from Example 117D (0.034g, 0.079 mmol), DEPBT (0.030 g, 0.099 mmol), andN,N-diisopropylethylamine (0.115 mL, 0.658 mmol), stirred at 25° C. for16 hours, and partitioned between chloroform and 10% Na₂CO₃ solution.The organic phase was washed with additional 10% Na₂CO₃ solution andbrine, dried over MgSO₄, filtered and concentrated. The residue waspurified by chromatography on silica gel eluting with 0-100% ethylacetate/dichloromethane, followed by 0-5% methanol in ethyl acetate togive the product (0.030 g, 54% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm0.82 (s, 9 H), 0.89 (s, 9 H), 1.21 (d, J=2.2 Hz, 3 H), 1.23 (d, J=2.2Hz, 3 H), 1.41-1.57 (m, 2 H), 2.33 (q, J=8.5 Hz, 1 H), 2.57 (m, 1 H),2.66 (d, J=7.0 Hz, 2 H), 2.79 (m, 1 H), 2.98 (m, 2 H), 3.19(m, 1 H),3.50(s, 3 H), 3.66 (m, 1 H), 3.85 (d, J=9.56 Hz, 1 H), 4.08 (s, 1H),4.13-4.25 (m, 2 H), 4.38 (m, 2 H), 4.53 (d, J=7.7 Hz, 1 H), 6.65 (d,J=9.55 Hz, 1 H), 7.03-7.13 (m, 7 H), 7.15-7.22 (m, 3H), 7.31 (m, 1 H),7.47 (d, J=9.56 Hz, 1 H), 7.71 (t, J=7.7 Hz, 1 H), 7.81-7.90 (m, 3 H),8.62 (m, 1 H).

EXAMPLE 132methyl(1S)-1-[({(1S,3S,4S)-1-benzyl-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-[4-(2-pyridinyl)phenyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamateEXAMPLE 132Atert-butyl(1S,3S,4S)-1-benzyl-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-[4-(2-pyridinyl)phenyl]pentylcarbamate

A solution containing the product from Example 23Q (0.074 mmol) in THF(0.8 mL) was treated with the product from Example 10D (0.032 g, 0.094mmol, DEPBT (0.035 g, 0.117 mmol), and N,N-diisopropylethylamine (0.10mL, 0.574 mmol), stirred at 25° C. for 1 hour, and partitioned betweenchloroform and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and then brine, dried over MgSO₄,filtered and concentrated. The product was purified by chromatography onsilica gel eluting with 0-100% ethyl acetate/dichloromethane, followedby 0-0.5% methanol in ethyl acetate to give the product (0.017 g, 31%yield).

EXAMPLE 132B(2S)—N-{(1S,2S,4S)-4-amino-2-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanamide

A solution containing the product from Example 132A (0.017 g, 0.023mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL),and the mixture was stirred at 25° C. for 1 hour, and concentrated. Theresidue was partitioned between ethyl acetate and saturated NaHCO₃, andthe organic phase was washed with brine and dried over MgSO₄, filteredand concentrated to give the product, which was used without furtherpurification.

EXAMPLE 132Cmethyl(1S)-1-[({(1S,3S,4S)-1-benzyl-4-[((2S)-3,3-dimethyl-2-{3-[(6-methyl-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl}butanoyl)amino]-3-hydroxy-5-[4-(2-pyridinyl)phenyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A solution containing the product from Example 132B (0.023 mmol) in THF(0.25 mL) were added the product from Example 1F (0.005 g, 0.026 mmol),DEPBT (0.010 g, 0.033 mmol), and N,N-diisopropylethylamine (0.020 mL,0.115 mmol), stirred at 25° C. for 16 hours, and partitioned betweenchloroform and 10% Na₂CO₃ solution. The organic phase was washed withadditional 10% Na₂CO₃ solution and then brine, dried over MgSO₄,filtered and concentrated. The product was purified by chromatography onsilica gel eluting with 0-100% ethyl acetate/dichloromethane, followedby 0-5% methanol in ethyl acetate to give the product. The product wasre-purified by preparative TLC eluting with 5% methanol in ethyl acetateto give the title compound (0.002 g, 11% yield). ¹H NMR (300 MHz,DMSO-d₆), δ ppm 0.82 (s, 9 H), 0.91 (s, 9 H), 1.25 (m, 1 H), 1.52 (m, 2H), 2.41 (m, 1 H), 2.43 (s, 3 H), 2.74 (m, 3H), 2.97 (q, J=9.2 Hz, 1 H),3.24 (m, 1 H), 3.54 (s, 3 H), 3.66 (m, 1 H), 3.82 (d, J=9.9 Hz, 2 H),4.09 (s, 1 H), 4.17 (m, 1 H), 4.25 (d, J=16 Hz, 1 H), 4.35 (d, J=16 Hz,1 H), 4.53 (d, J=7.4 Hz, 1 H), 6.63 (d, J=9.9 Hz, 1 H), 7.11 (m, 8 H),7.21 (d, J=8.09 Hz, 2 H), 7.51 (d, J=8.56 Hz, 1 H), 7.62 (t, J=7.7 Hz, 1H), 7.75 (m, 2H), 7.83 (d, J=8.09 Hz, 1 H), 8.60 (d, J=4.1 Hz, 1 H).

EXAMPLE 133methyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-disec-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamateEXAMPLE 133Atert-butyl(1S,2S,4S)-1-benzyl-4-[(tert-butoxycarbonyl)amino]-2-hydroxy-5-[4-(2-pyridinyl)phenyl]pentylcarbamate

To a solution of the product from Example 1B (7.32 g, 12.1 mmol) intoluene (400 mL) were treated with DPPA (5.2 mL, 24.2 mmol) andtriethylamine (3.4 mL, 24.4 mmol), heated at reflux for 2 hours, cooled,treated with tert-Butyl alcohol (41.6 mL), triethylamine (4 mL), andDMAP (0.30 g), heated at reflux for an additional 64 hours, cooled andconcentrated. A solution of the residue in THF (60 mL) was treated withTBAF solution in THF (36 mL, 1N), stirred at 25° C. for 40 hours,concentrated and partitioned between ethyl acetate and water. Theorganic phase was washed with brined, dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting with0-50% ethyl acetate in dichloromethane to give 0.614 g (9% yield) of thelower Rf product by TLC (25% ethyl acetate in dichloromethane).

EXAMPLE 133B(2S,3S,5S)-2,5-diamino-1-phenyl-6-[4-(2-pyridinyl)phenyl]-3-hexanol

A solution containing the product from Example 133A (0.60 g, 1.07 mmol)in dichloromethane (10 mL) was treated with trifluoroacetic acid (10mL), stirred at 25° C. for 1 hour, concentrated and partitioned betweenchloroform and saturated NaHCO₃. The organic was dried over Na₂SO₄,filtered and concentrated to give the title compound (0.386 g, 98%yield).

EXAMPLE 133Cmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-disec-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate

A solution containing the product from Example 133B (0.045 g, 0.125mmol) in DMF (1.2 mL) was treated with the product from Example 5A(0.060 g, 0.317 mmol), EDAC (0.075 g, 0.391 mmol), HOBT (0.050 g, 0.370mmol), and NMM (0.030 mL, 0.272 mmol), stirred at 25° C. for 16 hours,and partitioned between ethyl acetate and water. The organic phase waswashed with brine, dried over MgSO₄, filtered and concentrated. Theresidue was purified by reversed phase chromatography on a C18 column,eluting with 5-100% acetonitrile in water (0.1% TFA). The product waspartitioned between ethyl acetate and saturated NaHCO₃, and the organicphase was washed with brine and dried over MgSO₄, filtered andconcentrated to give the product (0.0072 g, 8% yield). ¹H NMR (300 MHz,DMSO-d₆), δ ppm 0.56 (d, J=7.0 Hz, 3H), 0.64 (t, J=7.0 Hz, 3H), 0.72 (t,J=8.5 Hz, 3H), 0.90-1.07 (m, 2H), 1.20-1.34 (m, 3H), 1.43-1.67 (m, 4H),2.57 (m, 1H), 2.69-2.77 (m, 3H), 3.50 (s, 3H), 3.53 (s, 3H), 3.60 (m,1H), 3.71-3.83 (m, 2H), 4.03-4.21 (m, 2H), 6.87 (d, J=9.2 Hz, 1H), 6.70(d, J=8.5 Hz, 1H), 7.10-7.21 (m, 7H), 7.30 (m, 1H), 7.70 (d, J=8.8 Hz,1H), 7.81-7.96 (m, 5H), 8.63 (m, 1H).

EXAMPLE 134methyl(1S)-1-({[(1S,2S,4S)-1-benzyl-2-hydroxy-4-({(2S)-3-methyl-2-[2-oxo-3-(4-quinolinylmethyl)-1-imidazolidinyl]pentanoyl}amino)-5-phenylpentyl]amino}carbonyl)-2,2-dimethylpropylcarbamateEXAMPLE 134A9H-fluoren-9-ylmethyl(1S,2S,4S)-1-benzyl-2-hydroxy-4-({(2S,3S)-3-methyl-2-[2-oxo-3-(4-quinolinylmethyl)-1-imidazolidinyl]pentanoyl}amino)-5-phenylpentylcarbamate

A solution containing the product from Example 3B (0.150 g, 0.276 mmol)in DMF (3 mL) was treated with the product from Example 4A (0.110 g,0.332 mmol), EDAC (0.080 g, 0.417 mmol), HOBT (0.055, 0.407 mmol), andNMM (0.090 mL, 0.819 mmol) at 0° C., stirred at 25° C. for 16 hours, andpartitioned between ethyl acetate and water. The organic phase waswashed with 10% citric acid, dilute sodium bicarbonate, and brine, driedover MgSO₄ filtered and concentrated. The residue was purified byreversed phase chromatography on a C18 column, eluting with 5-100%acetonitrile in water (0.1% TFA) to give the product (0.122 g, 53%yield).

EXAMPLE 134B(2S,3S)-N-[(1S,3S,4S)-4-amino-1-benzyl-3-hydroxy-5-phenylpentyl]-3-methyl-2-[2-oxo-3-(4-quinolinylmethyl)-1-imidazolidinyl]pentanamide

A solution containing the product from Example 134A (0.122 g, 0.147mmol) in DMF (6 mL) was treated with diethylamine (1.5 mL), stirred at25° C. for 1 hour, and partitioned between ethyl acetate and water. Theorganic phase was washed with brine and dried over MgSO₄, filtered andconcentrated to give the title compounds.

EXAMPLE 134Cmethyl(1S)-1-({[(1S,2S,4S)-1-benzyl-2-hydroxy-4-({(2S)-3-methyl-2-[2-oxo-3-(4-quinolinylmethyl)-1-imidazolidinyl]pentanoyl}amino)-5-phenylpentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate

A solution containing the product from Example 134B (0.147 mmol) in DMF(2 mL) was treated with the product from Example 1F (0.035 g, 0.185mmol), EDAC (0.045 g, 0.235 mmol), HOBT (0.030g, 0.222 mmol), and NMM(0.050 mL, 0.455 mmol) at 0° C., stirred at 25° C. for 16 hours, andpartitioned between ethyl acetate and water. The organic phase waswashed with 10% citric acid, dilute sodium bicarbonate, and brine, driedover MgSO₄, filtered and concentrated. The residue was purified byreversed phase chromatography on a C18 column, eluting with 5-100%acetonitrile in water (0.1% TFA) to give the title compound (0.019 g,17% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.68 (d, J=6.6 Hz, 3 H),0.93 (m, 12 H), 0.88-0.97 (m, 1 H), 1.22-1.33 (m, 1H), 1.47-1.56 (m,2H), 1.72-1.84 (m, 1H), 2.38-2.45 (m, 1H), 2.62-2.73 (m, 3H), 2.79-2.86(m, 1H), 2.98-3.10 (m, 3H), 3.55-3.63 (m, 4H), 3.89-3.94 (m, 2H),4.07-4.21 (m, 2H), 4.80 (s, 2H), 6.79 (d, J=9.56 Hz, 1 H), 6.93-7.20 (m,10 H), 7.41 (d, J=4.41 Hz, 1 H), 7.48-7.53 (m, 1H), 7.57-7.62 (m, 1H),7.75-7.80 (m, 1H), 7.87 (d, J=9.19 Hz, 1 H), 8.06 (d, J=8.45 Hz, 1 H),8.30 (d, J=8.08 Hz, 1 H), 8.88 (d, J=4.41 Hz, 1 H).

EXAMPLE 135methyl(1S)-1-({[(1S,3S,4S)-4({(2S)-2-[3-(2-fluorobenzyl)-2-oxoimidazolidin-1-yl]-3,3-dimethylbutanoyl}amino)-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamateEXAMPLE 135A tert-butylN-{2-[(2-fluorobenzyl)amino]ethyl}-3-methyl-L-valinate

A solution of Example 6F (0.124 g, 0.538 mmol) and 2-fluorobenzaldehyde(56.7 μL, 0.565 mmol) in methanol (2.5 mL) and benzene (2.5 mL) wasstirred at 50° C. for 16 h. The mixture was cooled to 25° C. and treatedwith sodium borohydride (40.7 mg, 1.076 mmol) for 2 h. The mixture waspartitioned between sodium bicarbonate and ethyl acetate. The organiclayer was separated, washed with brine, dried over MgSO₄, filtered andconcentrated to give the title compound as a clear oil (183 mg, 100%).

EXAMPLE 135Btert-butyl(2S)-2-[3-(2-fluorobenzyl)-2-oxoimidazolidin-1-yl]-3,3-dimethylbutanoate

A solution of Example 135A (183 mg, 0.54 mmol) and disuccinimidylcarbonate (0.165 g, 0.645 mmol) in dichloromethane (3 mL) was treatedwith triethylamine (90 uL, 0.645 mmol) at 25° C. for 16 h. The mixturewas partitioned between 10% sodium carbonate and dichloromethane. Theorganic layer was separated, washed with brine, dried over MgSO₄,filtered and concentrated to give the crude title compound (199 mg,crude yield).

EXAMPLE 135C(2S)-2-[3-(2-fluorobenzyl)-2-oxoimidazolidin-1-yl]-3,3-dimethylbutanoicacid

A solution of Example 135B (199 mg, 0.54 mmol) in dichloromethane (1.5mL) was treated with trifluoroacetic acid (1.5 mL) at 25° C. for 16 h.The solvents were evaporated, and the crude residue was purified usingreverse phase chromatography using 95% water (0.1% trifluoroaceticacid)/5% acetonitrile-100% acetonitrile to give the title compound(0.121 g, 73%).

EXAMPLE 135Dmethyl(1S)-1-({[(1S,3S,4S)-4({(2S)-2-[3-(2-fluorobenzyl)-2-oxoimidazolidin-1-yl]-3,3-dimethylbutanoyl}amino)-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate

A solution of Example 135C (32 mg, 0.103 mmol) and Example 2C (50 mg,0.094 mmol) in tetrahydrofuran (1 mL) was treated with DEPBT (42 mg,0.14 mmol), and diisopropylethylamine (82 μL, 0.47 mmol) at 25° C. for16 h. The crude residue was purified by silica gel chromatography usingdichloromethane to 100% ethyl acetate to 95% ethyl acetate/5% methanolto give the title compound (47 mg, 61%). ¹H NMR (300 MHz, DMSO-d₆) δ ppm0.83(s, 9H), 0.88(s, 9H), 1.58-1.49(m, 2H), 2.35-2.27(m, 1H),2.61-2.54(m, 1H), 2.67-2.65(d, J=6.99 Hz, 2H), 2.87-2.76(m, 2H),3.03-2.94(q, J=8.70 Hz, 1H), 3.20-3.16(m, 1H), 3.50(s, 3H), 3.70-3.63(m,1H), 3.86-3.83(d, J=9.93 Hz, 1H), 4.07(s, 1H), 4.23-4.10(m, 2H),4.46-4.28(m, 2H), 4.55-4.52(d, J=7.35 Hz, 1H), 6.65-6.62(d, J=9.56 Hz,1H), 7.09-6.99(m, 4H), 7.26-7.21(m, 4H), 7.40-7.28(m, 3H), 7.50-7.46(d,J=9.56 Hz, 1H), 7.91-7.82(m, 5H), 8.64-8.63(m, 1H).

EXAMPLE 136methyl(1S)-1-({[(1S,3S,4S)-4({(2S)-2-[3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl]-3,3-dimethylbutanoyl}amino)-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamateEXAMPLE 136A tert-butylN-{2-[(4-fluorobenzyl)amino]ethyl}-3-methyl-L-valinate

A solution of Example 6F (0.124 g, 0.538 mmol) and 4-fluorobenzaldehyde(60.6 μL, 0.565 mmol) in methanol (2.5 mL) and benzene (2.5 mL) wasstirred at 50° C. for 16 h. The mixture was cooled to 25° C. and treatedwith sodium borohydride (40.7 mg, 1.076 mmol) for 2 h. The mixture waspartitioned between sodium bicarbonate and ethyl acetate. The organiclayer was separated, washed with brine, dried over MgSO₄, filtered, andthe solvents were evaporated to give the title compound as a cruderesidue which was used directly in the next step.

EXAMPLE 136 Btert-butyl(2S)-2-[3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl]-3,3-dimethylbutanoate

A solution of Example 136A and disuccinimidyl carbonate (0.165 g, 0.645mmol) in dichloromethane (3 mL) was treated with triethylamine (90 μL,0.645 mmol) at 25° C. for 16 h. The mixture was partitioned between 10%sodium carbonate and dichloromethane. The organic layer was separated,washed with brine, dried over MgSO₄, filtered, and the solvents wereevaporated to give the crude title compound.

EXAMPLE 136C(2S)-2-[3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl]-3,3-dimethylbutanoicacid

A solution of Example 136B in dichloromethane (1.5 mL) was treated withtrifluoroacetic acid (1.5 mL) at 25° C. for 16 h. The solvents wereevaporated, and the crude residue was purified using reverse phasechromatography, eluting with a gradient of 95% water (0.1%trifluoroacetic acid)/5% acetonitrile to 100% acetonitrile to give thetitle compound (0.133 g, 80%).

EXAMPLE 136Dmethyl(1S)-1-({[(1S,3S,4S)-4-({(2S)-2-[3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl]-3,3-dimethylbutanoyl}amino)-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate

A solution of Example 136C (32 mg, 0.103 mmol) and Example 2C (50 mg,0.094 mmol) in tetrahydrofuran (1 mL) was treated with DEPBT (42 mg,0.14 mmol), and diisopropylethylamine (82 uL, 0.47 mmol) at 25° C. for16 h. The crude residue was purified by silica gel chromatographyeluting with a gradient of dichloromethane, 100% ethyl acetate, and 95%ethyl acetate/5% methanol to give the title compound (49 mg, 62%). ¹HNMR (300 MHz, DMSO-d₆) δ ppm 0.83(s, 9H), 0.88(s, 9H), 1.58-1.49(m, 2H),2.37-2.28(m, 1H), 2.61-2.54(m, 1H), 2.68-2.66(d, J=7.35 Hz, 2H),2.90-2.75(m, 2H), 2.98-2.87(q, J=8.46 Hz, 1H), 3.20-3.16(m, 1H), 3.50(s,3H), 3.70-3.63(m, 1H), 3.86-3.83(d, J=9.93 Hz, 1H), 4.08(s, 1H),4.21-4.13(m, 2H), 4.30(s, 2H), 4.56-4.54(d, J=7.35 Hz, 1H), 6.65-6.62(d,J=9.56 Hz, 1H), 7.12-7.03(m, 4H), 7.24-7.18(m, 4H), 7.34-7.29(m, 3H),7.49-7.46(d, J=9.56 Hz, 1H), 7.91-7.82(m, 5H), 8.64-8.63(m, 1H).

EXAMPLE 137methyl(1S)-1-({[(1S,3S,4S)-4({(2S)-2-[3-(3-fluorobenzyl)-2-oxoimidazolidin-1-yl]-3,3-dimethylbutanoyl}amino)-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamateEXAMPLE 137A tert-butylN-{2-[(3-fluorobenzyl)amino]ethyl}-3-methyl-L-valinate

A solution of Example 6F (0.14 g, 0.61 mmol) and 3-fluorobenzaldehyde(60.6 μL, 0.565 mmol) in methanol (2.5 mL) and benzene (2.5 mL) wasstirred at 50° C. for 16 h. The mixture was cooled to 25° C. and treatedwith sodium borohydride (46 mg, 1.2 mmol) for 2 h. The mixture waspartitioned between sodium bicarbonate and ethyl acetate. The organiclayer was separated, washed with brine, dried over MgSO₄, filtered andthe solvents were evaporated to give the title compound as a cruderesidue (0.199 g, 0.588 mmol) which was used directly in the next step.

EXAMPLE 137Btert-butyl(2S)-2-[3-(3-fluorobenzyl)-2-oxoimidazolidin-1-yl]-3,3-dimethylbutanoate

A solution of Example 137A (0.199 g, 0.588 mmol) and disuccinimidylcarbonate (0.181 g, 0.7 mmol) in dichloroethane (6 mL) was treated withtriethylamine (98 μL, 0.71 mmol) at 25° C. for 16 h. The mixture waspartitioned between 10% sodium carbonate and dichloromethane. Theorganic layer was separated, washed with brine, dried over MgSO₄,filtered and the solvents were evaporated to give the crude titlecompound.

EXAMPLE 137C(2S)-2-[3-(3-fluorobenzyl)-2-oxoimidazolidin-1-yl]-3,3-dimethylbutanoicacid

A solution of Example 137B in dichloromethane (1.5 mL) was treated withtrifluoroacetic acid (1.5 mL) at 25° C. for 16 h. The solvents wereevaporated, and the crude residue was purified using reverse phasechromatography eluting with a gradient of 95% water (0.1%trifluoroacetic acid)/5% acetonitrile to 100% acetonitrile to give thetitle compound (0.14 g, 74%).

EXAMPLE 137Dmethyl(1S)-1-({[(1S,3S,4S)-4-({(2S)-2-[3-(3-fluorobenzyl)-2-oxoimidazolidin-1-yl]-3,3-dimethylbutanoyl}amino)-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate

A solution of Example 137C (32 mg, 0.103 mmol) and Example 2C (50 mg,0.094 mmol) in tetrahydrofuran (1 mL) was treated with DEPBT (42 mg,0.14 mmol), and diisopropylethylamine (82 μL, 0.47 mmol) at 25° C. for16 h. The crude residue was purified by silica gel chromatographyeluting with a gradient of dichloromethane, 100% ethyl acetate, and 95%ethyl acetate/5% methanol to give the title compound (48 mg, 61%). ¹HNMR (300 MHz, DMSO-d₆) δ ppm 0.83(s, 9H), 0.89(s, 9H), 1.58-1.49(m, 2H),2.39-2.30(q, J=9.19 Hz, 1H), 2.62-2.54(m, 1H), 2.69-2.66(d, J=7.35 Hz,2H), 2.90-2.77(m, 2H), 3.02-2.93(q, J=8.7 Hz, 1H), 3.27-3.18(m, 1H),3.50(s, 3H), 3.70-3.63(m, 1H), 3.87-3.83(d, J=9.93 Hz, 1H), 4.09(s, 1H),4.19-4.14(m, 2H), 4.39-4.27(m, 2H), 4.56-4.54(d, J=7.72 Hz, 1H),6.65-6.62(d, J=9.56 Hz, 1H), 7.15-7.04(m, 8H), 7.24-7.21(d, J=8.46 Hz,2H), 7.33-7.29(m, 1H), 7.46-7.39(m, 1H), 7.53-7.50(d, J=9.56 Hz, 1H),7.91-7.82(m, 4H), 8.65-8.62(m, 1H).

EXAMPLE 138methyl(1S)-1-({[(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{2-oxo-3-[2-(trifluoromethyl)benzyl]imidazolidin-1-yl}butanoyl)amino]-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamateEXAMPLE 138A tert-butyl3-methyl-N-(2-{[2-(trifluoromethyl)benzyl]amino}ethyl)-L-valinate

A solution of Example 6F (0.137 g, 0.595 mmol) ando-trifluoromethyl-benzaldehyde (82 μL, 0.62 mmol) in methanol (2.5 mL)and benzene (2.5 mL) was stirred at 50° C. for 16 h. The mixture wascooled to 25° C. and treated with sodium borohydride (45 mg, 1.2 mmol)for 2 h. The mixture was partitioned between sodium bicarbonate andethyl acetate. The organic layer was separated, washed with brine, driedover MgSO₄, filtered, and the solvents were evaporated to give the titlecompound as a clear oil (225 mg, 100%).

EXAMPLE 138Btert-butyl(2S)-3,3-dimethyl-2-{2-oxo-3-[2-(trifluoromethyl)benzyl]imidazolidin-1-yl}butanoate

A solution of Example 138A (225 mg, 0.595 mmol) and disuccinimidylcarbonate (0.183 g, 0.714 mmol) in dichloroethane (6 mL) was treatedwith triethylamine (99 μL, 0.714 mmol) at 25° C. for 16 h. The mixturewas partitioned between 10% sodium carbonate and dichloromethane. Theorganic layer was separated, washed with brine, dried over MgSO₄,filtered, and the solvents were evaporated to give the crude titlecompound.

EXAMPLE 138C(2S)-3,3-dimethyl-2-{2-oxo-3-[2-(trifluoromethyl)benzyl]imidazolidin-1-yl}butanoicacid

A solution of Example 138B in dichloromethane (1.5 mL) was treated withtrifluoroacetic acid (1.5 mL) at 25° C. for 16 h. The solvents wereevaporated, and the crude residue was purified using reverse phasechromatography eluting with a gradient of 95% water (0.1%trifluoroacetic acid)/5% acetonitrile to 100% acetonitrile to give thetitle compound (0.121 g, 73%).

EXAMPLE 138Dmethyl(1S)-1-({[(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{2-oxo-3-[2-(trifluoromethyl)benzyl]imidazolidin-1-yl}butanoyl)amino]-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate

A solution of Example 137C (37 mg, 0.103 mmol) and Example 2C (50 mg,0.094 mmol) in tetrahydrofuran (1 mL) was treated with DEPBT (42 mg,0.14 mmol), and diisopropylethylamine (82 μL, 0.47 mmol) at 25° C. for16 h. The crude residue was purified by silica gel chromatographyeluting with a gradient of dichloromethane, 100% ethyl acetate, and 95%ethyl acetate/5% methanol to give the title compound (57 mg, 63%). ¹HNMR (300 MHz, DMSO-d₆) δ ppm 0.83(s, 9H), 0.91(s, 9H), 1.59-1.52(m, 2H),2.62-2.44(m, 2H), 2.71-2.68(d, J=6.99 Hz, 2H), 2.82-2.76(m, 1H),2.92-2.85(m, 1H), 3.07-2.99(q, J=9.19 Hz, 1H), 3.26-3.23(m, 1H), 3.50(s,3H), 3.71-3.62(m, 1H), 3.87-3.83(d, J=9.93 Hz, 1H), 4.10(s, 1H),4.25-4.13(m, 2H), 4.55-4.41(m, 2H), 4.58-4.55(d, J=7.72 Hz, 1H),6.65-6.62(d, J=9.93 Hz, 1H), 7.07-7.05(m, 3H), 7.15-7.12(m, 2H),7.24-7.21(d, J=8.09 Hz, 2H), 7.33-7.29(m, 1H), 7.55-7.49(m, 3H),7.78-7.70(dd, J=17.1, 7.91 Hz, 2H), 7.92-7.82(m, 4H), 8.64-8.63(m, 1H).

EXAMPLE 139methyl(1S)-1-({[(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{2-oxo-3-[4-(trifluoromethyl)benzyl]imidazolidin-1-yl}butanoyl)amino]-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamateEXAMPLE 139A tert-butyl3-methyl-N-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)-L-valinate

A solution of Example 6F (0.124 g, 0.538 mmol) andp-trifluoromethyl-benzaldehyde (86.8 μL, 0.647 mmol) in methanol (2.5mL) and benzene (2.5 mL) was stirred at 50° C. for 16 h. The mixture wascooled to 25° C. and treated with sodium borohydride (46.6 mg, 1.22mmol) for 2 h. The mixture was partitioned between sodium bicarbonateand ethyl acetate. The organic layer was separated, washed with brine,dried over MgSO₄, filtered, and the solvents were evaporated to give thetitle compound as a crude residue which was used directly in the nextstep.

EXAMPLE 139Btert-butyl(2S)-3,3-dimethyl-2-{2-oxo-3-[4-(trifluoromethyl)benzyl]imidazolidin-1-yl}butanoate

A solution of Example 139A and disuccinimidyl carbonate (0.19 g, 0.74mmol) in dichloromethane (6 mL) was treated with triethylamine (103 μL,0.74 mmol) at 25° C. for 16 h. The mixture was partitioned between 10%sodium carbonate and dichloromethane. The organic layer was separated,washed with brine, dried over MgSO₄, filtered, and the solvents wereevaporated to give the crude title compound (0.262 g).

EXAMPLE 139C(2S)-3,3-dimethyl-2-{2-oxo-3-[4-(trifluoromethyl)benzyl]imidazolidin-1-yl}butanoicacid

A solution of Example 139B (0.262 g) in dichloromethane (3 mL) wastreated with trifluoroacetic acid (3 mL) at 25° C. for 16 h. Thesolvents were evaporated, and the crude residue was purified usingreverse phase chromatography eluting with 95%water (0.1% trifluoroaceticacid)/5% acetonitrile to 100% acetonitrile to give the title compound(0.172 g, 78%).

EXAMPLE 139Dmethyl(1S)-1-({[(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{2-oxo-3-[4-(trifluoromethyl)benzyl]imidazolidin-1-yl}butanoyl)amino]-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate

A solution of Example 139C (37 mg, 0.103 mmol) and Example 2C (50 mg,0.094 mmol) in tetrahydrofuran (1 mL) was treated with DEPBT (42 mg,0.14 mmol), and diisopropylethylamine (82 uL, 0.47 mmol) at 25° C. for16 h. The crude residue was purified by silica gel chromatography usingdichloromethane to 100% ethyl acetate to 95% ethyl acetate/5% methanolto give the title compound (42 mg, 51%). ¹H NMR (300 MHz, DMSO-d₆) δ ppm0.83(s, 9H), 0.90(s, 9H), 1.58-1.49(m, 2H), 2.44-2.35(q, J=9.07 Hz, 1H),2.62-2.54(m, 1H), 2.69-2.67(d, J=6.99 Hz, 2H), 2.81-2.76(m, 1H),2.90-2.84(m, 1H), 3.09-2.95(q, J=8.70, 1H), 3.27-3.18(m, 1H), 3.50(s,3H), 3.70-3.63(m, 1H), 3.87-3.83(d, J=9.93 Hz 1H), 4.09(s, 1H),4.26-4.12(m, 2H), 4.41(s, 2H), 4.57-4.55(d, J=7.35 Hz, 1H), 6.66-6.62(d,J=10.30 Hz, 1H), 7.12-7.05(m, 5H), 7.24-7.21(d, J=8.09 Hz, 2H),7.33-7.29(m, 1H), 7.51-7.49(d, J=7.72 Hz, 3H), 7.76-7.73(d, J=8.46 Hz,2H), 7.91-7.82(m, 4H), 8.64-8.63(d, J=4.41 Hz, 1H).

EXAMPLE 140methyl(1S)-1-({[(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{2-oxo-3-[3-(trifluoromethyl)benzyl]imidazolidin-1-yl}butanoyl)amino]-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamateEXAMPLE 140A tert-butyl3-methyl-N-(2-{[3-(trifluoromethyl)benzyl]amino}ethyl)-L-valinate

A solution of Example 6F (0.143 g, 0.623 mmol) andm-trifluoromethyl-benzaldehyde (87.5 μL, 0.654 mmol) in methanol (2.5mL) and benzene (2.5 mL) was stirred at 50° C. for 16 h. The mixture wascooled to 25° C. and treated with sodium borohydride (47 mg, 1.25 mmol)for 2 h. The mixture was partitioned between sodium bicarbonate andethyl acetate. The organic layer was separated, washed with brine, driedover MgSO₄, filtered and the solvents were evaporated to give the titlecompound as a crude residue which was used directly in the next step.

EXAMPLE 140Btert-butyl(2S)-3,3-dimethyl-2-{2-oxo-3-[3-(trifluoromethyl)benzyl]imidazolidin-1-yl}butanoate

A solution of Example 140A and disuccinimidyl carbonate (0.192 g, 0.75mmol) in dichloromethane (6 mL) was treated with triethylamine (104 μL,0.75 mmol) at 25° C. for 16 h. The mixture was partitioned between 10%sodium carbonate and dichloromethane. The organic layer was separated,washed with brine, dried over MgSO₄, filtered, and the solvents wereevaporated to give the crude title compound (0.261 g, 100%).

EXAMPLE 140C(2S)-3,3-dimethyl-2-{2-oxo-3-[3-(trifluoromethyl)benzyl]imidazolidin-1-yl}butanoicacid

A solution of Example 140B (0.261 g, 0.623 mmol) in dichloromethane (3mL) was treated with trifluoroacetic acid (3 mL) at 25° C. for 16 h. Thesolvents were evaporated, and the crude residue was purified usingreverse phase chromatography eluting with 95% water (0.1%trifluoroacetic acid)/5% acetonitrile to 100% acetonitrile to give thetitle compound (0.172 g 77%).

EXAMPLE 140Dmethyl(1S)-1-({[(1S,3S,4S)-4-[((2S)-3,3-dimethyl-2-{2-oxo-3-[3-(trifluoromethyl)benzyl]imidazolidin-1-yl}butanoyl)amino]-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate

A solution of Example 140C (37 mg, 0.103 mmol) and Example 2C (50 mg,0.094 mmol) in tetrahydrofuran (1 mL) was treated with DEPBT (42 mg,0.14 mmol), and diisopropylethylamine (82 μL, 0.47 mmol) at 25° C. for16 h. The crude residue was purified by silica gel chromatographyeluting with dichloromethane, 100% ethyl acetate, and 95% ethylacetate/5% methanol to give the title compound (55 mg, 67%). ¹H NMR (300MHz, DMSO-d₆) δ ppm 0.83(s, 9H), 0.90(s, 9H), 1.58-1.49(m, 2H),2.34-2.25(q, J=9.44 Hz, 1H), 2.62-2.54(m, 1H), 2.68-2.65(d, J=7.35 Hz,2H), 2.81-2.76(m, 1H), 3.00-2.86(m, 2H), 3.22-3.16(m, 1H), 3.50(s, 3H),3.70-3.63(m, 1H), 3.87-3.83(d, J=9.56 Hz 1H), 4.09(s, 1H), 4.26-4.12(m,2H), 4.42(s, 2H), 4.55-4.53(d, J=7.35 Hz, 1H), 6.66-6.62(d, J=9.93 Hz,1H), 7.10-7.01(m, 5H), 7.24-7.21(d, J=8.46 Hz, 2H), 7.33-7.29(m, 1H),7.54-7.51(d, J=9.56 Hz, 1H), 7.68-7.58(m, 4H), 7.91-7.82(m, 4H),8.64-8.63(d, J=4.41 Hz, 1H).

EXAMPLE 141methyl(1S)-1-({[(1S,3S,4S)-4-({(2S)-2-[3-(2-amino-3-methylbenzyl)-2-oxoimidazolidin-1-yl]-3,3-dimethylbutanoyl}amino)-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamateEXAMPLE 141A 3-methyl-2-nitrobenzaldehyde

A solution of 3-methyl-2-nitrobenzyl alcohol (0.4 g, 2.4 mmol) inacetonitrile (8 mL) was treated with Dess-Martin reagent (1.11 g, 2.63mmol) at 25° C. for 16 h. The mixture was quenched with sodiumbicarbonate/sodium thiosulfate (1:1, 15 mL), and the mixture wasextracted with dichloromethane, the organic layer separated, washed withbrine, dried over sodium sulfate, filtered, and the solvents wereevaporated to give the crude title compound (0.387 g, 98%).

EXAMPLE 141B tert-butyl3-methyl-N-{2-[(3-methyl-2-nitrobenzyl)amino]ethyl}-L-valinate

A solution of Example 6F (0.148 g, 0.64 mmol) and3-methyl-2-nitrobenzaldehyde (116.5 mg, 0.705 mmol) in methanol (2.5 mL)and benzene (2.5 mL) was stirred at 50° C. for 16 h. The mixture wascooled to 25° C. and treated with sodium borohydride (48 mg, 1.28 mmol)for 2 h. The mixture was partitioned between sodium bicarbonate andethyl acetate. The organic layer was separated, washed with brine, driedover MgSO₄, filtered and the solvents were evaporated to give the titlecompound as a crude residue which was used directly in the next step.

EXAMPLE 141Ctert-butyl(2S)-3,3-dimethyl-2-[3-(3-methyl-2-nitrobenzyl)-2-oxoimidazolidin-1-yl]butanoate

A solution of Example 141B and disuccinimidyl carbonate (0.197 g, 0.77mmol) in dichloromethane (6 mL) was treated with triethylamine (107 μL,0.79 mmol) at 25° C. for 16 h. The mixture was partitioned between 10%sodium carbonate and dichloromethane. The organic layer was separated,washed with brine, dried over MgSO₄, filtered, and the solvents wereevaporated to give the crude title compound.

EXAMPLE 141D(2S)-3,3-dimethyl-2-[3-(3-methyl-2-nitrobenzyl)-2-oxoimidazolidin-1-yl]butanoicacid

A solution of Example 141 C in dichloromethane (3 mL) was treated withtrifluoroacetic acid (3 mL) at 25° C. for 16 h. The solvents wereevaporated, and the crude residue was purified using reverse phasechromatography eluting with 95% water (0.1% trifluoroacetic acid)/5%acetonitrile to 100% acetonitrile to give the title compound (0.172 g,77%).

EXAMPLE 141E methyl(1S)-1-({[(1S,3S,4S)-4-({(2S)-2-[3-(2-nitro-3-methylbenzyl)-2-oxoimidazolidin-1-yl]-3,3-dimethylbutanoyl}amino)-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate

A solution of Example 141D (36 mg, 0.103 mmol) and Example 2C (50 mg,0.094 mmol) in tetrahydrofuran (1 mL) was treated with DEPBT (42 mg,0.14 mmol), and diisopropylethylamine (82 μL, 0.47 mmol) at 25° C. for16 h. The crude residue was purified by silica gel chromatographyeluting with a gradient of dichloromethane, 100% ethyl acetate, and 95%ethyl acetate/5% methanol to give the title compound (64 mg, 79%).

EXAMPLE 141Fmethyl(1S)-1-({[(1S,3S,4S)-4-({(2S)-2-[3-(2-amino-3-methylbenzyl)-2-oxoimidazolidin-1-yl]-3,3-dimethylbutanoyl}amino)-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate

A solution of Example 141E (64 mg, 0.074 mmol) in ethanol (2 mL) wastreated with 10% Pd/C (23.6 mg, 0.022 mmol) with a hydrogen balloon at25° C. for 16 h. The catalyst was filtered through Celite®, rinsed withethanol, and the solvents were evaporated. The crude residue waspurified using reverse phase chromatography eluting with a gradient of95% water (0.1% trifluoroacetic acid)/5% acetonitrile to 100%acetonitrile to give the title compound (0.051 g, 83%). ¹H NMR (300 MHz,DMSO-d₆) δ ppm 0.83(s, 9H), 0.87(s, 9H), 1.58-1.49(m, 2H), 2.12(s, 3H),2.23-2.12(m, 1H), 2.61-2.54(m, 1H), 2.66-2.64(d, J=7.35 Hz, 2H),2.88-2.81(m, 2H), 3.02-2.93(q, J=8.58 Hz, 1H), 3.18-3.12(m, 1H), 3.48(s,3H), 3.69-3.65(m, 1H), 3.86-3.82(d, J=9.93 Hz, 1H), 4.05(s, 1H),4.33-4.13(m, 4H), 6.65-6.58(m, 2H), 6.99-6.90(m, 4H), 7.08-7.05(d,J=7.72 Hz, 2H), 7.28-7.25(d, J=8.46 Hz, 2H), 7.37-7.33(d, J=9.93 H, 1H),7.46-7.42(m, 1H), 7.90-7.83(m, 2H), 8.03-7.90(m, 2H), 8.69-8.67(d,J=4.78 Hz, 1H).

EXAMPLE 142methyl(1S,4S,5S,7S,10S)-4benzyl-10-tert-butyl-5-hydroxy-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-1-[(3R)-tetrahydrofuran-3-yl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamateEXAMPLE 142AN¹-[(1S,3S,4S)-4-({(2S)-2-azido-2-[(3R)-tetrahydrofuran-3-yl]ethanoyl}amino)-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]-N²-(methoxycarbonyl)-3-methyl-L-valinamide

A solution of the product of Example 2C (0.050 g, 0.094 mmol) intetrahydrofuran (1.0 mL) was treated with 2(S)-azido2-(3(R)-tetrahydrofuranyl)acetic acid (J. Med. Chem. 1993, 36,2300-2310) (0.020 g, 0.117 mmol), DEPBT (0.045 g, 0.151 mmol), andN,N-diisopropylethylamine (0.080 mL, 0.459 mmol), stirred at 25° C. for12 hours and partitioned between ethyl acetate and 10% Na₂CO₃ solution.The organic layer was washed with additional 10% Na₂CO₃ solution andbrine, dried over MgSO₄, filtered and concentrated. The residue waschromatographed on silica gel eluting with a gradient starting withchloroform and ending with 5% methanol in ethyl acetate to give thetitle compound (0.041 g, 64% yield).

EXAMPLE 142Bmethyl(1S,4S,5S,7S,10S)-4benzyl-10-tert-butyl-5-hydroxy-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-1-[(3R)-tetrahydrofuran-3-yl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate

To a solution of the product of Example 142A (0.038 g, 0.055 mmol) in amixture of methanol (0.40 mL) and ethyl acetate (0.40 mL) was added 10%Pd on C (0.038 g), and the reaction was stirred under an atmosphere ofhydrogen (balloon pressure) for 2 hours. The mixture was filteredthrough celite and the solvent was evaporated. The residue was dissolvedin dichloromethane (0.40 mL) and pyridine (0.007 mL, 0.087 mmol) andmethyl chloroformate (0.004 mL, 0.052 mmol) were added and the mixturewas stirred at room temperature for 1 hour. The reaction was dilutedwith ethyl acetate and the organic layer was washed with dilute NaHCO₃,and brine, dried over MgSO₄, filtered and concentrated. The residue waschromatographed on silica gel eluting with a gradient starting withchloroform and ending with 5% methanol in ethyl acetate to give thetitle compound (0.017 g, 43% yield). ¹H NMR (300 MHz, MeOH-d₄), δ ppm0.87 (s, 9 H), 1.51-1.66 (m, 4 H), 2.31-2.43 (m, 1 H), 2.66 (dd, J=13.4,9.0 Hz, 1 H), 2.83-2.96 (m, 3 H), 3.44 (dd, J=6.4, 9.0 Hz, 1 H), 3.52(s, 3 H), 3.55-3.85 (m, 5 H), 3.65 (s, 3 H), 3.91 (d, J=9.6 Hz, 1 H),4.24-4.30 (m, 1 H), 4.34-4.42 (m, 1 H), 7.11-7.35 (m, 8 H), 7.78-7.90(m, 4 H), 8.57 (m, 1 H).

EXAMPLE 143methyl(1S)-1-({[(1S,3S,4S)-3-hydroxy-4-({(2S)-2-[3-(3-hydroxybenzyl)-2-oxoimidazolidin-1-yl]-3,3-dimethylbutanoyl}amino)-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamateEXAMPLE 143A tert-butylN-{2-[(3-hydroxybenzyl)amino]ethyl}-3-methyl-L-valinate

A solution of Example 6F (0.052 g, 0.226 mmol) and m-hydroxybenzaldehyde(30.3 mg, 0.248 mmol) in methanol (1.25 mL) and benzene (1.25 mL) wasstirred at 50° C. for 16 h. The mixture was cooled to 25° C. and treatedwith sodium borohydride (19 mg, 0.496 mmol) for 2 h. The mixture waspartitioned between sodium bicarbonate and ethyl acetate. The organiclayer was separated, washed with brine, dried over MgSO₄, filtered, andthe solvents were evaporated to give the title compound as a cruderesidue (0.073 g, 96%) which was used directly in the next step.

EXAMPLE 143Btert-butyl(2S)-2-[3-(3-hydroxybenzyl)-2-oxoimidazolidin-1-yl]-3,3-dimethylbutanoate

A solution of Example 143A (0.073 g, 0.23 mmol) and disuccinimidylcarbonate (0.069 g, 0.27 mmol) in dichloroethane (3 mL) was treated withtriethylamine (38 μL, 0.27 mmol) at 25° C. for 16 h. The mixture waspartitioned between 10% sodium carbonate and dichloromethane. Theorganic layer was separated, washed with brine, dried over MgSO₄,filtered, and the solvents were evaporated to give the crude titlecompound (0.026 g, 32%).

EXAMPLE 143C(2S)-2-[3-(3-hydroxybenzyl)-2-oxoimidazolidin-1-yl]-3,3-dimethylbutanoicacid

A solution of Example 143B (0.026 g, 0.072 mmol) in dichloromethane (1.5mL) was treated with trifluoroacetic acid (1.5 mL) at 25° C. for 16 h.The solvents were evaporated, and the crude residue was purified usingreverse phase chromatography eluting with a gradient of 95% water (0.1%trifluoroacetic acid)/5% acetonitrile to 100% acetonitrile to give thetitle compound (0.022 g, 100%).

EXAMPLE 143Dmethyl(1S)-1-({[(1S,3S,4S)-3-hydroxy-4-({(2S)-2-[3-(3-hydroxybenzyl)-2oxoimidazolidin-1-yl]-3,3-dimethylbutanoyl}amino)-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate

A solution of Example 143C (22 mg, 0.072 mmol) and Example 2C (25.4 mg,0.048 mmol) in tetrahydrofuran (1 mL) was treated with DEPBT (21 mg,0.072 mmol), and diisopropylethylamine (42 μL, 0.24 mmol) at 25° C. for16 h. The crude residue was purified by silica gel chromatographyeluting with a gradient of dichloromethane, 100% ethyl acetate, and 95%ethyl acetate/5% methanol to give the title compound (12 mg, 30%). ¹HNMR (300 MHz, DMSO-d₆) 0.83(s, 9H), 0.89(s, 9H), 1.58-1.49(m, 2H),2.35-2.26(m, 1H), 2.61-2.54(m, 1H), 2.68-2.66(d, J=6.99, 2H),2.86-2.76(m, 2H), 2.98-2.89(m, 1H), 3.19-3.13(m, 1H), 3.50(s, 3H),3.70-3.63(m, 1H), 3.87-3.83(d, J=9.93 Hz, 1H), 4.08(s, 1H), 4.27-4.14(m,4H), 4.56-4.54(d, J=7.35 Hz, 1H), 6.69-6.63(m, 3H), 7.17-7.04(m, 7H),7.24-7.21(d, J=8.46 Hz, 2H), 7.33-7.29(m, 1H) 7.46-7.43(d, J=9.56 Hz,1H), 7.91-7.82(m, 5H), 8.64(m, 1H), 9.39(s, 1H).

EXAMPLE 144methyl(1S)-1-({[(1S,3S,4S)-3-hydroxy-4-({(2S)-2-[3-(4-hydroxybenzyl)-2-oxoimidazolidin-1-yl]-3,3-dimethylbutanoyl}amino)-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamateEXAMPLE 144A tert-butylN-{2-[(4-hydroxybenzyl)amino]ethyl}-3-methyl-L-valinate

A solution of Example 6F (0.075 g, 0.326 mmol) and p-hydroxybenzaldehyde(44 mg, 0.358 mmol) in methanol (1.6 mL) and benzene (1.6 mL) wasstirred at 50° C. for 16 h. The mixture was cooled to 25° C. and treatedwith sodium borohydride (25 mg, 0.651 mmol) for 2 h. The mixture waspartitioned between sodium bicarbonate and ethyl acetate. The organiclayer was separated, washed with brine, dried over MgSO₄, filtered, andthe solvents were evaporated to give the title compound as a cruderesidue (0.1 g, 100%) which was used directly in the next step.

EXAMPLE 144Btert-butyl(2S)-2-[3-(4-hydroxybenzyl)-2-oxoimidazolidin-1-yl]-3,3-dimethylbutanoate

A solution of Example 144A (0.1 g, 0.32 mmol) and disuccinimidylcarbonate (0.1 g, 0.39 mmol) in dichloroethane (3 mL) was treated withtriethylamine (91 μL, 0.65 mmol) at 25° C. for 16 h. The mixture waspartitioned between 10% sodium carbonate and dichloromethane. Theorganic layer was separated, washed with brine, dried over MgSO₄,filtered, and the solvents were evaporated and the crude residue waspurified using silica gel chromatography eluting with a gradient of 100%hexanes to 60% hexanes in ethyl acetate to give the title compound(0.046 g, 39%).

EXAMPLE 144C(2S)-2-[3-(4-hydroxybenzyl)-2-oxoimidazolidin-1-yl]-3,3-dimethylbutanoicacid

A solution of Example 144B (0.04 g, 0.11 mmol) in dichloromethane (0.5mL) was treated with trifluoroacetic acid (0.5 mL) at 25° C. for 16 h.The solvents were evaporated, and the crude residue was twice azeotropedwith ethyl acetate to give the crude title compound (0.034 g, 100%).

EXAMPLE 144Dmethyl(1S)-1-({[(1S,3S,4S)-3-hydroxy-4-({(2S)-2-[3-(4-hydroxybenzyl)-2-oxoimidazolidin-1-yl]-3,3-dimethylbutanoyl}amino)-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate

A solution of Example 144C (34 mg, 0.11 mmol) and Example 2C (53.2 mg,0.1 mmol) in tetrahydrofuran (1 mL) was treated with DEPBT (45 mg, 0.15mmol), and diisopropylethylamine (87 μL, 0.5 mmol) at 25° C. for 16 h.The crude residue was purified using reverse phase chromatographyeluting with a gradient of 95% water(0.1% trifluoroacetic acid)/5%acetonitrile to 100% acetonitrile to give the title compound (10 mg,12%). ¹H NMR (300 MHz, DMSO-d₆) 0.83(s, 9H), 0.89(s, 9H), 1.58-1.51(m,2H), 2.33-2.24(m, 1H), 2.61-2.54(m, 1H), 2.67-2.65(d, J=7.35, 2H),2.81-2.77(m, 2H), 2.94-2.85(m, 1H), 3.14(m, 1H), 3.50(s, 3H), 3.66(m,1H), 3.86-3.83(d, J=9.93 Hz, 1H), 4.07(s, 1H), 4.24-4.13(m, 4H),6.66-6.63(d, J=9.53 Hz, 1H), 6.75-6.72(d, J=8.46 Hz, 2H), 7.09-7.02(m,7H), 7.24-7.21(d, J=8.09 Hz, 2H), 7.33-7.30(m, 1H), 7.46-7.43(d, J=9.93Hz, 1H), 7.91-7.82(m, 5H), 8.65(m, 1H), 9.34(s, 1H).

EXAMPLE 145methyl(1S)-1-({[(1S,3S,4S)-3-hydroxy-4-({(2S)-2-[3-(2-hydroxybenzyl)-2-oxoimidazolidin-1-yl]-3,3-dimethylbutanoyl}amino)-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamateEXAMPLE 145A tert-butylN-{2-[(2-hydroxybenzyl)amino]ethyl}-3-methyl-L-valinate

A solution of Example 6F (0.12 g, 0.521 mmol) and o-hydroxybenzaldehyde(60 μL, 0.573 mmol) in methanol (2.5 mL) and benzene (2.5 mL) wasstirred at 50° C. for 16 h. The mixture was cooled to 25° C. and treatedwith sodium borohydride (40 mg, 1.04 mmol) for 2 h. The mixture waspartitioned between sodium bicarbonate and ethyl acetate. The organiclayer was separated, washed with brine, dried over MgSO₄, filtered, andthe solvents were evaporated to give the title compound as a clear oil(180 mg, 100%).

EXAMPLE 145Btert-butyl(2S)-2-[3-(2-hydroxybenzyl)-2-oxoimidazolidin-1-yl]-3,3-dimethylbutanoate

A solution of Example 145A (180 mg, 0.521 mmol) and disuccinimidylcarbonate (0.16 g, 0.625 mmol) in dichloroethane (5 mL) was treated withtriethylamine (87 μL, 0.625 mmol) at 25° C. for 16 h. The mixture waspartitioned between 10% sodium carbonate and dichloromethane. Theorganic layer was separated, washed with brine, dried over MgSO₄,filtered, and the solvents were evaporated to give the crude residuewhich was purified using silica gel chromatography eluting with agradient of 100% hexanes to 60% hexanes in ethyl acetate to give thetitle compound (0.127 g, 67%).

EXAMPLE 145C(2S)-2-[3-(2-hydroxybenzyl)-2-oxoimidazolidin-1-yl]-3,3-dimethylbutanoicacid

A solution of Example 145B (0.127 g, 0.35 mmol) in dichloromethane (1.75mL) was treated with trifluoroacetic acid (1.75 mL) at 25° C. for 16 h.The solvents were evaporated, and the crude residue was azeotroped twicewith ethyl acetate to give crude material which was used directly in thenext step.

EXAMPLE 145Dmethyl(1S)-1-({[(1S,3S,4S)-3-hydroxy-4-({(2S)-2-[3-(2-hydroxybenzyl)-2-oxoimidazolidin-1-yl]-3,3-dimethylbutanoyl}amino)-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate

A solution of Example 145C and Example 2C (58 mg, 0.12 mmol) intetrahydrofuran (1.1 mL) was treated with DEPBT (49 mg, 0.163 mmol), anddiisopropylethylamine (95 μL, 0.545 mmol) at 25° C. for 16 h. The cruderesidue was purified by silica gel chromatography eluting with agradient of dichloromethane, 100% ethyl acetate to 95% ethyl acetate/5%methanol, to afford the title compound (45 mg, 50%). ¹H NMR (300MHz,DMSO-d₆) δ ppm 0.83(s, 9H), 0.88(s, 9H), 1.62-1.48(m, 2H), 2.36-2.27(m,1H), 2.61-2.54(m, 1H), 2.67-2.64(d, J=6.99, 2H), 2.81-2.79(m, 1H),2.95-2.84(m, 1H), 3.07-2.95(m, 1H), 3.21-3.17(m, 1H), 3.50(s, 3H),3.70-3.63(m, 1H), 3.87-3.83(d, J=9.93 Hz, 1H), 4.07(s, 1H), 4.15(m, 2H),4.34-4.4.24(m, 2H), 4.55-4.53(d, J=7.72 Hz, 1H), 6.66-6.63(d, J=9.93 Hz,1H), 6.85-6.77(m, 2H), 7.02(m, 3H), 7.13-7.08(m, 4H), 7.24-7.21(d,J=8.09 Hz, 2H), 7.33-7.29(m, 1H), 7.48-7.45(d, J=9.93 Hz, 1H),7.91-7.82(m, 5H), 8.64-8.63(d, J=4.78 Hz, 1H), 9.56(s, 1H).

EXAMPLE 146methyl(1S,4S,5S,7S,10S)-4benzyl-1,10-di-tert-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(1,3-thiazol-2-yl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamateEXAMPLE 146Atert-butyl(1S,2S,4S)-4-amino-1-benzyl-2-{[tert-butyl(dimethyl)silyl]oxy}-5-[4-(1,3-thiazol-2-yl)phenyl]pentylcarbamate

To a solution containing the product from Example 92D (0.050 g, 0.070mmol) in N,N-dimethylformamide (1.8 mL) were added silver(I) oxide(0.016 g, 0.070 mmol), tetrakis(triphenylphosphine)palladium (0.004 g,0.003 mmol), and 2-tributylstannylthiazole (0.126 g, 0.337 mmol), andthe mixture was irradiated at 60 W in a microwave (internal temperaturereached 100° C.) for 2 minutes. The mixture was then irradiated at 200 Win a microwave (internal temperature reached 100° C.) for 4 minutes Thereaction was cooled, diluted with chloroform and washed with diluteNaHCO₃, and brine, dried over MgSO₄, filtered and concentrated. Theresidue was chromatographed on silica gel eluting with 30% methanol inchloroform containing 0.2% ammonium hydroxide to give the title compound(0.053 g).

EXAMPLE 146BN¹-{(1S,3S,4S)-4-[(tert-butoxycarbonyl)amino]-3-{[tert-butyl(dimethyl)silyl]oxy}-5-phenyl-1-[4-(1,3-thiazol-2-yl)benzyl]pentyl}-N²-(methoxycarbonyl)-3-methyl-L-valinamide

To a solution containing the product from Example 146A (0.053 g) intetrahydrofuran (0.70 mL) were added the product from Example 1F (0.015g, 0.079 mmol), DEPBT (0.033 g, 0.110 mmol), andN,N-diisopropylethylamine (0.065 mL, 0.373 mmol) and the mixture wasstirred at room temperature for 1 hour. The mixture was partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic was washedwith additional 10% Na₂CO₃ solution and then brine, dried over MgSO₄,filtered and evaporated. The residue was chromatographed on silica geleluting with a gradient starting with chloroform and ending with 80 %ethyl acetate in chloroform to give the product (0.042 g).

EXAMPLE 146CN¹-{(1S,3S,4S)-4-amino-3-hydroxy-5-phenyl-1-[4-(1,3-thiazol-2-yl)benzyl]pentyl}-N²-(methoxycarbonyl)-3-methyl-L-valinamide

To the product from Example 146B (0.042 g, 0.056 mmol) was addedtetrabutyl ammonium fluoride solution in tetrahydrofuran (0.28 mL, 1N)and the mixture was stirred at room temperature for 18 hours. Thetetrahydrofuran was evaporated and the mixture was partitioned betweenethyl acetate and water. The organic was washed with brine, dried overMgSO₄, filtered and evaporated. The residue was dissolved indichloromethane (0.40 mL) and trifluoroacetic acid (0.20 mL) was addedand the mixture was stirred at room temperature for 30 minutes. Thesolvent was evaporated and the residue was partitioned betweenchloroform and dilute NaHCO₃, and brine, dried over MgSO₄, filtered andconcentrated to give the title compound (0.035 g), which was usedwithout further purification.

EXAMPLE 146Dmethyl(1S,4S,5S,7S,10S)-4benzyl-1,10-di-tert-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(1,3-thiazol-2-yl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate

To a solution containing the product from Example 146C (0.035 g, 0.065mmol) in tetrahydrofuran (0.70 mL) were added the product from Example1F (0.012 g, 0.063 mmol), DEPBT (0.029 g, 0.097 mmol), andN,N-diisopropylethylamine (0.056 mL, 0.321 mmol) and the mixture wasstirred at room temperature for 3 hours. The mixture was partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic was washedwith additional 10% Na₂CO₃ solution and then brine, dried over MgSO₄,filtered and evaporated. The residue was chromatographed on reversephase HPLC on a C18 column, eluting with a gradient starting with water(containing 0.1% trifluoroacetic acid) and ending with acetonitrile togive the product (0.021 g, 46% yield). ¹H NMR (300 MHz, MeOH-d₆), δ ppm0.86 (s, 9 H), 0.88 (s, 9 H), 1.61-1.71 (m, 2 H), 2.58-2.65 (m, 1 H),2.76-2.96 (m, 4 H), 3.57 (s, 3H), 3.65 (s, 3 H), 3.74-3.79 (m, 1 H),3.81 (s, 1 H), 3.1 (s, 1 H), 4.19-4.28 (m, 1 H), 4.30-4.40 (m, 1 H),7.10-7.28 (m, 7 H), 7.56 (d, J=3.3 Hz, 1 H), 7.78 (d, J=8.1 Hz, 2 H),7.83 (d, J=3.3 Hz, 1 H).

EXAMPLE 147methyl(1S,4S,5S,7S,10S)-4benzyl-10-tert-butyl-5-hydroxy-1-[(1S)-1-methylpropyl]-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate

A solution of Example 5A (8.9 mg, 0.047 mmol) and Example 2C (25 mg,0.047 mmol) in tetrahydrofuran (0.5 mL) was treated with DEPBT (21 mg,0.07 mmol), and diisopropylethylamine (41 μL, 0.235 mmol) at 25° C. for16 h. The crude residue was purified by silica gel chromatographyeluting with a gradient of dichloromethane, 100% ethyl acetate to 95%ethyl acetate/5% methanol to give the title compound (23 mg, 69%). ¹HNMR (300 MHz, DMSO-d₆) 0.66-0.64(d, J=6.62 Hz, 3H), 0.76-0.71(t, J=7.35Hz, 3H), 0.80(s, 9H), 1.03-0.93(m, 1H), 1.29-1.23(m, 1H), 1.62-1.44(m,2H), 2.56-2.51(m, 1H), 2.77-2.71(m, 3H), 3.49(s, 3H), 3.49(m, 1H),3.54(s, 3H), 3.62(m, 1H), 3.79(m, 1H), 3.84-3.81(d, J=9.56 Hz, 1H),4.15-4.06(m, 2H), 4.92-4.90(d, J=5.52 Hz, 1H), 6.64-6.61(d, J=9.56 Hz,1H), 7.05-7.02(d, J=9.19 Hz, 1H), 7.21-7.10(m, 6H), 7.33-7.29(m, 1H),7.45-7.42(d, J=9.19 Hz, 1H), 7.82-7.78(d, J=8.46 Hz, 1H), 7.90-7.83(m,5H), 8.64(m, 1H).

EXAMPLE 148methyl(1S,4S,5S,7S,10S)-4benzyl-1,10-di-tert-butyl-5-hydroxy-2,9,12-trioxo-7-(4-pyridin-3-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamateEXAMPLE 148Atert-butyl(1S,2S,4S)-1-benzyl-4-{[(benzyloxy)carbonyl]amino}-2-{[tert-butyl(dimethyl)silyl]oxy}-5-(4-pyridin-3-ylphenyl)pentylcarbamate

To a solution containing the product from Example 92D (0.50 g, 0.70mmol) in N,N-dimethylformamide (7.0 mL) were added lithium chloride(0.30 g, 7.08 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.150g, 0.214 mmol), and 3-tributylstannylpyridine (0.776 g, 2.11 mmol), andthe mixture was heated to 100° C. for 18 hours. The reaction wasfiltered, diluted with ethyl acetate and washed with water, and brine,dried over MgSO₄, filtered and concentrated. The residue waschromatographed on silica gel eluting with a gradient starting withchloroform and ending with 25% ethyl acetate in chloroform to give thetitle compound (0.365 g).

EXAMPLE 148Btert-butyl(1S,2S,4S)-1-benzyl-4-{[(benzyloxy)carbonyl]amino}-2-hydroxy-5-(4-pyridin-3-ylphenyl)pentylcarbamate

To the product from Example 148A (0.365 g, 0.51 mmol) was addedtetrabutyl ammonium fluoride solution in tetrahydrofuran (2.0 mL, 1N)and the mixture was stirred at room temperature for 18 hours. Thetetrahydrofuran was evaporated and the mixture was partitioned betweenethyl acetate and water. The organic was washed with brine, dried overMgSO₄, filtered and evaporated. The residue was chromatographed onsilica gel eluting with a gradient starting with chloroform and endingwith 80% ethyl acetate in chloroform to give the title compound (0.172g, 41% over two steps).

EXAMPLE 148Ctert-butyl(1S,2S,4S)-4-amino-1-benzyl-2-hydroxy-5-(4-pyridin-3-ylphenyl)pentylcarbamate

The product from Example 148B (0.170 g, 0.29 mmol) was dissolved in amixture of ethyl acetate (1.5 mL) and methanol (1.5 mL) and 20% Pd(OH)₂on carbon (0.080 g) and a solution of HCl in dioxane (0.070 mL, 4 N)were added, and the reaction was stirred under an atmosphere of hydrogen(balloon pressure) for 18 hours. The mixture was filtered throughcelite® and the solvent was evaporated to give the title compound as thehydrochloride salt, which was used without further purification.

EXAMPLE 148Dtert-butyl(1S,2S,4S)-1-benzyl-2-hydroxy-4-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-5-(4-pyridin-3-ylphenyl)pentylcarbamate

To a solution containing the product from Example 148C (0.29 mmol) intetrahydrofuran (3.0 mL) were added the product from Example 1F (0.060g, 0.317 mmol), DEPBT (0.130 g, 0.435 mmol), andN,N-diisopropylethylamine (0.25 mL, 1.44 mmol) and the mixture wasstirred at room temperature for 3 hours. The mixture was partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic was washedwith additional 10% Na₂CO₃ solution and then brine, dried over MgSO₄,filtered and evaporated. The residue was chromatographed on silica geleluting with a gradient starting with 50% ethyl acetate in chloroformand ending with 80% ethyl acetate in chloroform to give the product(0.108 g, 59% yield).

EXAMPLE 148EN¹-[(1S,3S,4S)-4-amino-3-hydroxy-5-phenyl-1-(4-pyridin-3-ylbenzyl)pentyl]-N²-(methoxycarbonyl)-3-methyl-L-valinamide

To a solution of the product of Example 148D (0.108 g, 0.17 mmol) indichloromethane (2.0 mL) was added trifluoroacetic acid (0.5 mL), andthe mixture was stirred at room temperature for 1 hour. The solvent wasevaporated, and the reaction was partitioned between ethyl acetate anddiluted NaHCO₃ solution. The organic layer was washed with brine, driedover MgSO₄, filtered and concentrated.

EXAMPLE 148Fmethyl(1S,4S,5S,7S,10S)-4benzyl-1,10-di-tert-butyl-5-hydroxy-2,9,12-trioxo-7-(4-pyridin-3-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate

To a solution containing the product from Example 148E (0.17 mmol) intetrahydrofuran (1.7 mL) were added the product from Example 1F (0.036g, 0.190 mmol), DEPBT (0.077 g, 0.258 mmol), andN,N-diisopropylethylamine (0.15 mL, 0.861 mmol) and the mixture wasstirred at room temperature for 18 hours. The mixture was partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic was washedwith additional 10% Na₂CO₃ solution and then brine, dried over MgSO₄,filtered and evaporated. The residue was chromatographed on reversephase HPLC on C18 column eluting with a gradient starting with water andending with methanol to give the product (0.044 g, 37% yield). ¹H NMR(300 MHz, DMSO-d₆), δ ppm 0.80 (s, 9 H), 0.82 (s, 9 H), 1.42-1.59 (m, 2H), 2.67-2.79 (m, 3 H), 3.47 (s, 3 H), 3.59-3.67 (m, 1 H), 3.81 (d,J=9.6 Hz, 1 H), 3.91 (d, J=9.6 Hz, 1 H), 4.02-4.21 (m, 2 H), 4.87 (d,J=5.2 Hz, 1 H), 6.65 (d, J=9.6 Hz, 1 H), 6.80 (d, J=9.9 Hz, 1 H),7.12-7.23 (m, 8 H), 7.45-7.55 (m, 4 H), 7.80 (d, J=8.5 Hz, 1 H), 8.01(d, J=8.1 Hz, 1 H), 8.54 (d, J=4.8 Hz, 1 H), 8.83 (d, J=1.8 Hz, 1 H).

EXAMPLE 149methyl(1S)-1-({[(1S,3S,4S)-3-hydroxy-4-{[(2S)-2-methyl-3-(methylsulfonyl)propanoyl]amino}-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamateEXAMPLE 149A (2S)-2-methyl-3-(methylthio)propanoic acid

A solution of D-(−)-3-acetyl-b-mercaptoisobutyric acid (0.3 g, 1.85mmol) in 5M KOH in methanol (0.74 mL, 3.7 mmol) at 0° C. was stirred for25 minutes. The mixture was treated with dimethyl sulfate (0.233 g, 1.85mmol) and allowed to warm to 25° C. for 1.5 h. The mixture was filteredthrough Celite® and rinsed with methanol. The solvents were evaporated,and the crude residue was partitioned between water and ethyl acetate.The aqueous layer was separated, acidified with 1N HCl, and extractedwith ethyl acetate. The organic layer was dried over MgSO₄, filtered,and the solvents were evaporated to give the crude title compound (0.14g, 56%).

EXAMPLE 149B (2S)-2-methyl-3-(methylsulfonyl)propanoic acid

A solution of Example 149A (0.085 g, 0.63 mmol) in acetone (1.2 mL) andwater (0.25 mL) at 0° C. was treated with oxone (1.17 g, 1.9 mmol) andthe mixture was stirred at 25° C. for 3 h. The mixture was filtered,rinsed with acetone, and the solvents were evaporated. The residue wasdissolved in ethyl acetate, dried over MgSO₄, filtered and the solventswere evaporated to give the crude title compound (47 mg, 45%).

EXAMPLE 149Cmethyl(1S)-1-({[(1S,3S,4S)-3-hydroxy-4-{[(2S)-2-methyl-3-(methylsulfonyl)propanoyl]amino}-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate

A solution of Example 149B (47 mg, 0.283 mmol) in N,N-dimethylformamide(1 mL) at 0° C. was treated with 1-hydroxybenzotriazole hydrate (57.3mg, 0.42 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDAC) (48.2 mg, 0.311 mmol), diisopropylethylamine (59μL, 0.34 mmol) and Example 2C (0.15 mg, 0.28 mmol) for 3 h at 25° C.,then for 16 h at 0° C. The mixture was partitioned between ethyl acetateand 5% potassium bisulfate, the organic layer was separated, washed withsaturated sodium bicarbonate, brine, dried over MgSO₄, filtered, and thesolvents were evaporated. The crude residue was purified by silica gelchromatography eluting with dichloromethane, 100% ethyl acetate, and 95%ethyl acetate/5% methanol to give the title compound (19 mg, 10%). ¹HNMR (300 MHz, CDCl₃) δ ppm 0.93(s, 9H), 1.21-1.18(d, J=6.99 Hz, 3H),1.71-1.57(m, 2H), 2.57(s, 3H), 2.88-2.76(m, 5H), 3.66-3.48(m, 1H),3.63(s, 3H), 3.79-3.70(m, 2H), 4.06-4.99(m, 2H), 4.27-4.20(m, 1H),5.38-5.35(d, J=8.82 Hz, 1H), 6.22-6.20(d, J=6.99 Hz, 1H), 6.39-6.32(d,J=9.19 Hz, 1H), 7.27-7.14(m, 8H), 7.77-7.67(m, 2H), 7.89-7.86(d, J=8.46Hz, 2H), 8.67-8.66(d, J=4.04 Hz, 1H).

EXAMPLE 150methyl(1S,4S,5S,7S,10S)-4benzyl-1,10-di-tert-butyl-5-hydroxy-2,9,12-trioxo-7-(4-pyridin-4-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamateEXAMPLE 150Atert-butyl(1S,2S,4S)-1-benzyl-4-{[(benzyloxy)carbonyl]amino}-2-{[tert-butyl(dimethyl)silyl]oxy}-5-(4-pyridin-4-ylphenyl)pentylcarbamate

To a solution containing the product from Example 92D (0.50 g, 0.70mmol) in N,N-dimethylformamide (7.0 mL) were added lithium chloride(0.30 g, 7.08 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.150g, 0.214 mmol), and 4-tributylstannylpyridine (0.776 g, 2.11 mmol), andthe mixture was heated to 100° C. for 18 hours. The reaction wasfiltered, diluted with ethyl acetate and washed with water, and brine,dried over MgSO₄, filtered and concentrated. The residue was dissolvedin acetonitrile and washed twice with hexanes, and the acetonitrilelayer was evaporated to give the title compound (0.422 g).

EXAMPLE 150Btert-butyl(1S,2S,4S)-1-benzyl-4-{[(benzyloxy)carbonyl]amino}-2-hydroxy-5-(4-pyridin-4-ylphenyl)pentylcarbamate

To the product from Example 150A (0.422 g, 0.60 mmol) was addedtetrabutyl ammonium fluoride solution in tetrahydrofuran (2.3 mL, 1N)and the mixture was stirred at room temperature for 18 hours. Thetetrahydrofuran was evaporated and the mixture was partitioned betweenethyl acetate and water. The organic was washed with brined, dried overMgSO₄ filtered and evaporated. The residue was chromatographed on silicagel eluting with a gradient starting with chloroform and ending with 80%ethyl acetate in chloroform to give the title compound (0.242 g, 58%over two steps).

EXAMPLE 150Ctert-butyl(1S,2S,4S)-4-amino-1-benzyl-2-hydroxy-5-(4-pyridin-4-ylphenyl)pentylcarbamate

The product from Example 150B (0.242 g, 0.41 mmol) was dissolved in amixture of ethyl acetate (2.0 mL) and methanol (2.0 mL) and 20% Pd(OH)₂on carbon (0.10 g) and a solution of HCl in dioxane (0.10 mL, 4 N) wereadded, and the reaction was stirred under an atmosphere of hydrogen(balloon pressure) for 18 hours. The mixture was filtered through celiteand the solvent was evaporated to give the title compound as thehydrochloride salt (0.273 g, which was used without furtherpurification.

EXAMPLE 150Dtert-butyl(1S,2S,4S)-1-benzyl-2-hydroxy-4-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-5-(4-pyridin-4-ylphenyl)pentylcarbamate

To a solution containing the product from Example 150C (0.41 mmol) intetrahydrofuran (4.0 mL) were added the product from Example 1F (0.085g, 0.450 mmol), DEPBT (0.183 g, 0.612 mmol), andN,N-diisopropylethylamine (0.36 mL, 2.07 mmol) and the mixture wasstirred at room temperature for 3 hours. The mixture was partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic was washedwith additional 10% Na₂CO₃ solution and then brine, dried over MgSO₄,filtered and evaporated. The residue was chromatographed on silica geleluting with a gradient starting with chloroform and ending with 80%ethyl acetate in chloroform to give the product (0.138 g, 53% yield).

EXAMPLE 150EN¹-[(1S,3S,4S)-4-amino-3-hydroxy-5-phenyl-1-(4-pyridin-4-ylbenzyl)pentyl]-N²-(methoxycarbonyl)-3-methyl-L-valinamide

To a solution of the product of Example 150D (0.138 g, 0.22 mmol) indichloromethane (2.0 mL) was added trifluoroacetic acid (0.5 mL), andthe mixture was stirred at room temperature for 1 hour. The solvent wasevaporated, and the reaction was partitioned between ethyl acetate anddiluted NaHCO₃ solution. The organic layer was washed with brine, driedover MgSO₄, filtered and concentrated.

EXAMPLE 150Fmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-di-tert-butyl-5-hydroxy-2,9,12-trioxo-7-(4-pyridin-4-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate

To a solution containing the product from Example 150E (0.22 mmol) intetrahydrofuran (2.5 mL) were added the product from Example 1F (0.046g, 0.243 mmol), DEPBT (0.099 g, 0.331 mmol), andN,N-diisopropylethylamine (0.19 mL, 1.09 mmol) and the mixture wasstirred at room temperature for 68 hours. The mixture was partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic was washedwith additional 10% Na₂CO₃ solution and then brine, dried over MgSO₄,filtered and evaporated. The residue was chromatographed on reversephase HPLC on a C18 column, eluting with a gradient starting with waterand ending with methanol to give the title compound (0.108 g, 70%yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.79 (s, 9 H), 0.82 (s, 9 H),1.42-1.59 (m, 2 H), 2.71-2.79 (m, 3 H), 3.48 (s, 3 H), 3.55 (s, 3 H),3.61-3.67 (m, 1 H), 3.81 (d, J=9.9 Hz, 1 H), 3.91 (d, J=9.6 Hz, 1 H),4.03-4.20 (m, 2 H), 4.87 (d, J=5.2 Hz, 1 H), 6.64 (d, J=9.6 Hz, 1 H),6.80 (d, J=9.6 Hz, 1 H), 7.12-7.23 (m, 8 H), 7.50-7.60 (m, 4 H), 7.65(d, J=5.9 Hz, 2 H), 7.80 (d, J=8.5 Hz, 1 H), 8.61 (d, J=5.9 Hz, 2 H).

EXAMPLE 151methyl(1S)-1-({[(1S,3S,4S)-3-hydroxy-4-{[(2S)-2-hydroxy-3,3-dimethylbutanoyl]amino}-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate

A solution of the product of Example 2C (0.020 g, 0.038 mmol) intetrahydrofuran (0.40 mL) was treated with(s)-(−)-2-hydroxy-3,3-dimethylbutyric acid (0.006 g, 0.045 mmol), DEPBT(0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.035 mL, 0.201mmol), stirred at 25° C. for 2 hours and partitioned between ethylacetate and 10% Na₂CO₃ solution. The organic layer was washed withadditional 10% Na₂CO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting witha gradient starting with dichloromethane and ending with ethyl acetateto give the title compound (0.005 g, 21% yield). ¹H NMR (300 MHz,DMSO-d₆), δ ppm 0.70 (s, 9 H), 0.79 (s, 9 H), 1.42-1.54 (m, 2 H),2.71-2.76 (m, 3 H), 3.42 (d, J=5.9 Hz, 1 H), 3.48 (s, 3 H), 3.61-3.67(m, 1 H), 3.82 (d, J=9.9 Hz, 1 H), 4.10-4.21 (m, 2 H), 4.98 (d, J=5.5Hz, 1 H), 5.33 (d, J=5.8 Hz, 1 H), 6.65 (d, J=9.6 Hz, 1 H), 7.09-7.24(m, 9 H), 7.28-7.32 (m, 1 H), 7.80 (d, J=8.5 Hz, 1 H), 7.84-7.89 (m, 4H), 8.62 (m, 1 H).

EXAMPLE 152methyl(1S,4S,6S,7S,10S)-7-benzyl-1,10-di-tert-butyl-6-hydroxy-12,12-dioxido-2,9-dioxo-4-(4-pyridin-2-ylbenzyl)-12-thia-3,8,11-triazatridec-1-ylcarbamateEXAMPLE 152A tert-butyl 3-methyl-N-(methylsulfonyl)-L-valinate

A solution of tert-butyl 3-methyl-L-valinate (50 mg, 0.223 mmol) indichloromethane (1 mL) at 0° C. was treated with4-(dimethylamino)pyridine (5.4 mg, 0.045 mmol), triethylamine (93.4 μL,0.67 mmol), and methanesulfonyl chloride (34.5 L, 0.45 mmol), and themixture was warmed to 25° C. for 1 h. The mixture was washed with 5%potassium bisulfate, saturated sodium bicarbonate, brine, and dried overMgSO₄, filtered, and the solvents were evaporated to give the crudetitle compound (59 mg, 100%).

EXAMPLE 152B 3-methyl-N-(methylsulfonyl)-L-valine

A solution of Example 152A (59 mg, 0.22 mmol) in 4N HCl in dioxane (1mL) at 25° C. for 4 h, and the solvents were evaporated to give thecrude title compound (49 mg, 100%).

EXAMPLE 152Cmethyl(1S,4S,6S,7S,10S)-7-benzyl-1,10-di-tert-butyl-6-hydroxy-12,12-dioxido-2,9-dioxo-4-(4-pyridin-2-ylbenzyl)-12-thia-3,8,11-triazatridec-1-ylcarbamate

A solution of Example 152B (22.7 mg, 0.108 mmol) inN,N-dimethylformamide (0.2 mL) was treated with 1-hydroxybenzotriazolehydrate (HOBT) (21 mg, 0.153 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC) (18.2mg, 0.117 mmol), Example 2C (48 mg, 0.09 mmol), anddiisopropylethylamine (79 μL, 0.45 mmol) at 0° C. After 1 h the mixturewas warmed to 25° C. for 16 h. The solvents were evaporated, and thecrude residue was purified using reverse phase chromatography elutingwith a gradient of 95% water (0.1% trifluoroacetic acid)/5% acetonitrileto 100% acetonitrile to give the title compound (15 mg, 23%). ¹H NMR(300 MHz, CDCl₃) δ ppm 0.92(s, 9H), 0.95(s, 9H), 1.70-1.56(m, 2H),2.47(bs, 3H), 2.91-2.77(m, 5H), 3.43-3.37(m, 1H), 3.64(s, 3H), 3.70(m,1H), 4.29-4.12(m, 2H), 5.20(m, 1H), 5.31(m, 1H), 6.15-6.12(d, J=8.09 Hz,1H), 6.21(m, 1H), 7.24-7.13(m, 8H), 7.79-7.68(m, 2H), 7.89-7.86(d,J=8.09 Hz, 2H), 8.69-8.67(d, J=4.78 Hz, 1H).

EXAMPLE 153methyl(1R,4S,5S,7S,10S)-4-benzyl-10-tert-butyl-5-hydroxy-1-[(methylthio)methyl]-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamateEXAMPLE 153A N-(methoxycarbonyl)-S-methyl-L-cysteine

A solution of L-cysteine (50 mg, 0.413 mmol) in methanol (0.4 mL) wastreated with 1N NaOH (0.45 mL, 0.45 mmol) and methyl iodide (28.3 μL,0.45 mmol) at 0° C. The mixture was warmed to 25° C. over 16 h, recooledto 0° C., and treated with 3N NaOH (0.45 μL, 1.3 mmol) and methylchloroformate (64 μL, 0.83 mmol) at 25° C. for 4 h. The mixture wasacidified with 2N HCl, and partitioned between ethyl acetate and water.The organic layer was separated, washed with water, brine, and driedover MgSO₄ and filtered. The solvents were evaporated to give the crudetitle compound (60 mg, 75%).

EXAMPLE 153Bmethyl(1R,4S,5S,7S,10S)-4-benzyl-10-tert-butyl-5-hydroxy-1-[(methylthio)methyl]-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate

A solution of Example 153A (25 mg, 0.129 mmol) in N,N-dimethylformamide(0.3 μL) was treated with 1-hydroxybenzotriazole hydrate (HOBT) (24.8mg, 0.18 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDAC) (21.7 mg, 0.14 mmol), Example 2C (57.4 mg, 0.107mmol), and diisopropylethylamine (94 μL, 0.54 mmol) at 25° C. for 16 h.The solvents were evaporated and the crude residue was dissolved inethyl acetate, washed with saturated sodium bicarbonate, brine, driedover MgSO₄ and filtered. The solvents were evaporated, and the cruderesidue was purified by silica gel chromatography eluting with agradient of dichloromethane to 100% ethyl acetate to give the titlecompound (48 mg, 63%). ¹H NMR (300 MHz, CDCl₃) δ ppm 0.93(s, 9H),1.67-1.62(m, 2H), 2.05(s, 3H), 2.72-2.70(d, J=6.25 Hz, 2H), 2.80-2.76(m,1H), 2.93-2.86(m, 3H), 3.62(s, 3H), 3.68(s, 3H), 3.78-3.75(m, 2H),4.05-3.97(m, 1H), 4.22-4.15(m, 2H), 5.33-5.30(d, J=8.82 Hz, 1H),5.58-5.55(d, J=6.25 Hz, 1H), 6.15-6.12(d, J=7.35 Hz, 1H), 6.63-6.60(d,J=8.82 Hz, 1H), 7.24-7.16(m, 8H), 7.77-7.68(m, 2H), 7.89-7.86(d, J=8.46Hz, 2H), 8.68-8.66(m, 1H).

EXAMPLE 154methyl(1R,4S,5S,7S,10S)-4-benzyl-10-tert-butyl-5-hydroxy-1-[(methylsulfonyl)methyl]-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate

A solution of Example 153B (20 mg, 0.028 mmol) in methanol (0.28 mL) andwater (0.28 mL) was treated with oxone (52 mg, 0.082 mmol) at 25° C. for1 h. The solvents were evaporated, and the residue was partitionedbetween ethyl acetate/water, the organic layer was separated, washedwith brine, dried over MgSO₄, filtered, and the solvents wereevaporated. The crude residue was purified by silica gel chromatographyeluting with a gradient of dichloromethane, 100% ethyl acetate, to 95%ethyl acetate/5% methanol to give the title compound (9 mg, 43%). ¹H NMR(300 MHz, MeOH-D6) δ ppm 0.86(s, 9H), 1.69-1.60(m, 2H), 2.70-2.63(m,1H), 2.89-2.82(m, 3H), 2.93(s, 3H), 3.3-3.23(m, 1H), 3.45-3.39(m, 1H),3.53(s, 3H), 3.67(s, 3H), 3.77-3.73(t, J=6.62 Hz, 1H), 3.81(s, 1H),4.27-4.22(m, 1H), 4.33(m, 1H), 4.63-4.59(dd, J=8.09, 4.78 Hz, 1H),7.19-7.12(m, 1H), 7.24-7.23(d, J=4.41 Hz, 4H), 7.30-7.27(d, J=8.09 Hz,2H), 7.35-7.30(m, 1H), 7.80-7.78(d, J=8.09 Hz, 2H), 7.82(m, 1H),7.87-7.84(dd, J=6.99, 1.84 Hz, 1H), 8.58-8.57(d, J=4.04 Hz, 1H).

EXAMPLE 155methyl(1R)-1-{[((1S,2S,4S)-4-{[4-(aminosulfonyl)benzoyl]amino}-1-benzyl-2-hydroxy-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamate

A solution of benzenesulfonamide-4-carboxylic acid (0.1 g, 0.49 mmol)and Example 23S (0.22 g, 0.48 mmol) in tetrahydrofuran (8 mL) wastreated with DEPBT (0.22 g, 0.73 mmol) and diisopropylethylamine (0.32g, 2.4 mmol) at 25° C. The mixture was stirred for 16 h and partitionedbetween 10% sodium carbonate and dichloromethane. The organic layer wasseparated, dried over sodium sulfate, and the solvents were evaporated.The crude residue was purified by chromatography on silica gel elutingwith 30% ethyl acetate in dichloromethane to give the title compound(0.17 g, 55% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm 0.85-0.95 (m, 9 H),2.74-3.08 (m, 5 H), 3.60 (s, 3 H), 3.65-3.71 (m, 1 H), 3.78 (s, 2 H),4.07 (s, 2 H), 4.31 (s, 1 H), 5.27 (d, J=8.82 Hz, 1 H), 6.29 (d, J=8.82Hz, 1 H), 6.81 (d, J=7.35 Hz, 1 H), 7.09 (s, 1 H), 7.11-7.25 (m, 10 H),7.64 (d, J=8.46 Hz, 2 H), 7.80 (d, J=8.46 Hz, 2 H).

EXAMPLE 156 methyl(1S)-1-({[(1S,3S,4S)-3-hydroxy-4-{[(2R)-2-hydroxy-3-methyl-3-(methylsulfonyl)butanoyl]amino}-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamateEXAMPLE 156AN-[(9H-fluoren-9-ylmethoxy)carbonyl]-3-(methylthio)-L-valine

To a solution of L-penicillamine (0.60 g, 4.02 mmol) in mixture of water(20 mL) and dioxane (20.0 mL) at room temperature were added potassiumcarbonate (11.04 g, 79.9 mmol) and methyl iodide (0.31 mL, 4.98 mmol),and the mixture was stirred for 1 hour. 9⁻fluorenylmethyl succinimidylcarbonate (5.39 g, 16.0 mmol) was added, and the reaction was stirred atroom temperature for 12 hours. The reaction was evaporated, and theresidue was partitioned between ether and water, and the mixture wasadjusted to pH 3 with 2 N HCl. The organic was washed with brine anddried over MgSO₄, filtered and evaporated. The residue waschromatographed on silica gel eluting with a gradient starting withdichloromethane and ending with 10% methanol in dichloromethane to givethe product (2.13 g).

EXAMPLE 156BN-[(9H-fluoren-9-ylmethoxy)carbonyl]-3-(methylsulfonyl)-L-valine

To a solution of the product from Example 156A (2.13 g) in mixture ofwater (11 mL) and acetone (5.5 mL) at room temperature were added sodiumbicarbonate (3.7 g, 44.0 mmol) and sodium hydroxide solution (6.6 mL, 1N). To this mixture was added a solution of oxone in water (4.75 g in 15mL) dropwise at room temperature and the reaction was stirred for 2hours. Ethyl acetate was added and the solution was adjusted to pH 3with concentrated HCl. The organic was washed with brine and dried overMgSO₄, filtered and evaporated. The residue was chromatographed onsilica gel eluting with a gradient starting with dichloromethane andending with 20% methanol in dichloromethane to give the product (0.70 g,42% over 2 steps).

EXAMPLE 156C (2R)-2-hydroxy-3-methyl-3-(methylsulfonyl)butanoic acid

To a solution of the product from Example 156B (0.35 g, 0.838 mmol) inN,N-dimethylformamide (3.0 mL) was added piperidine (0.17 mL, 1.72mmol), and this mixture was stirred at room temperature for 1 hour. Thereaction mixture was partitioned between dichloromethane and water. Theisolated organic layer was washed with brine and dried over MgSO₄,filtered and evaporated. The residue dissolved in water (1.0 mL) andconcentrated sulfuric acid (0.10 mL) was added at room temperature,followed by heating to 50° C. A solution of sodium nitrite (0.25 g) inwater (0.60 mL) was added dropwise at 50° C. and the reaction wasstirred for 1 hour. The reaction was extracted with ethyl acetate andwashed with water and brine. The organic was dried over MgSO₄, filteredand evaporated to give the crude product (0.041 g, 25% yield), which wasused without further purification.

EXAMPLE 156Dmethyl(1S)-1-({[(1S,3S,4S)-3-hydroxy-4-{[(2R)-2-hydroxy-3-(methylsulfonyl)butanoyl]amino}-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate

To a solution containing the product from Example 2C (0.020 g, 0.038mmol) in tetrahydrofuran (0.40 mL) were added the product from Example156C (0.008 g, 0.041 mmol), DEPBT (0.015 g, 0.050 mmol), andN,N-diisopropylethylamine (0.020 mL, 0.115 mmol) and the mixture wasstirred at room temperature for 1 hour. The mixture was partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic was washedwith additional 10% Na₂CO₃ solution and then brine, dried over MgSO₄,filtered and evaporated. The residue was chromatographed on silica geleluting with a gradient starting with dichloromethane and ending with50% acetone in dichloromethane to give the product (0.015 g, 56% yield).¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.81 (s, 9 H), 0.97 (s, 3 H), 1.01 (s,3 H), 1.49-1.53 (m, 2 H), 2.53-2.60 (m, 1 H), 2.76-2.81 (m, 3 H), 2.93(s, 3 H), 3.49 (s, 3 H), 3.64-3.70 (m, 1 H), 3.83 (d, J=9.9 Hz, 1 H),4.21 (d, J=6.3 Hz, 1 H), 4.17-4.30 (m, 2 H), 4.98 (d, J=5.5 Hz, 1 H),6.28 (d, J=6.3 Hz, 1 H), 6.67 (d, J=9.92 Hz, 1 H), 7.12-7.33 (m, 9 H),7.52 (d, J=9.6 Hz, 1 H), 7.80-7.91 (m, 5 H), 8.64 (d, J=4.8 Hz, 1 H).

EXAMPLE 157methyl(1S)-1-({[(1R,3S,4S)-4-[(4-chloro-2-methylbenzoyl)amino]-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate

A solution of 4-chloro-o-toluic acid (8.4 mg, 0.47 mmol) inN,N-dimethylformamide (0.3 mL) was treated with Example 1H (25 mg, 0.047mmol), 1-hydroxybenzotriazole hydrate (HOBT) (7.6 mg, 0.056 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC) (11mg, 0.07 mmol), diisopropylethylamine (16.4 μL, 0.09 mmol) at 25° C. for16 h. The solvents were evaporated, and the crude residue purified bysilica gel chromatography eluting with a gradient of dichloromethane,100% ethyl acetate, and 95% ethyl acetate/5% methanol to give the titlecompound (24 mg, 75%). ¹H NMR (300 MHz, CDCl₃) δ ppm 0.81(s, 9H),1.45-1.38(m, 1H), 1.88-1.79(m, 1H), 2.18(s, 3H), 2.89-2.85(m, 2H),2.98-2.96(m, 2H), 3.67(s, 3H), 3.74-3.60(m, 2H), 4.33-4.25(m, 1H),4.47-4.36(m, 1H), 5.31-5.28(d, J=8.46 Hz, 1H), 5.96-5.93(d, J=8.82 Hz,1H), 6.12-6.09(d, J=9.19 Hz, 1H), 7.02-6.94(m, 2H), 7.10(bs, 1H),7.33-7.15(m, 8H), 7.71-7.68(m, 1H), 7.86-7.81(m, 1H), 7.91-7.89(d,J=8.09 Hz, 2H), 8.76-8.74(d, J=4.04 Hz, 1H).

EXAMPLE 158methyl(1S)-1-({[(1R,3S,4S)-3-hydroxy-4-[(4-methoxy-2-methylbenzoyl)amino]-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate

A solution of 4-methoxy-2-methyl benzoic acid (8.2 mg, 0.49 mmol) inN,N-dimethylformamide (0.3 mL) was treated with Example 1H (25 mg, 0.047mmol), 1-hydroxybenzotriazole hydrate (HOBT) (7.6 mg, 0.056 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC) (11mg, 0.07 mmol), diisopropylethylamine (16.4 μL, 0.09 mmol) at 25° C. for16 h. The solvents were evaporated, and the crude residue purified bysilica gel chromatography eluting with a gradient of dichloromethane,100% ethyl acetate, and 95% ethyl acetate/5% methanol to give the titlecompound (25.8 mg, 80%). ¹H NMR (300 MHz, CDCl₃) δ ppm 0.80(s, 9H),1.46-1.38(m, 1H), 1.91-1.82(m, 1H), 2.27(s, 3H), 2.91-2.77(m, 2H),2.99-2.96(m, 2H), 3.74-3.59(m, 2H), 3.67(s, 3H), 3.73(s, 3H),4.32-4.24(m, 1H), 4.44-4.37(m, 1H), 4.50(m, 1H), 5.29-5.26(d, J=8.82 Hz,1H), 5.96-5.93(d, J=8.46 Hz, 1H), 6.13-6.10(d, J=9.19 Hz, 1H),6.59-6.55(dd, J=8.46, 2.57 Hz, 1H), 6.65(d, J=2.21 Hz, 1H), 7.08-7.06(d,J=8.46 Hz, 1H), 7.25-7.14(m, 8H), 7.68-7.66(m, 1H), 7.77-7.72(m, 1H),7.92-7.90(d, J=8.46 Hz, 2H), 8.70-8.68(d, J=4.04 Hz, 1H).

EXAMPLE 159methyl(1S)-1-({[(1R,3S,4S)-3-hydroxy-4-[(2-methylbenzoyl)amino]-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate

A solution of o-toluic acid (6.7 mg, 0.49 mmol) in N,N-dimethylformamide(0.3 mL) was treated with Example-1H (25 mg, 0.047 mmol),1-hydroxybenzotriazole hydrate (HOBT) (7.6 mg, 0.056 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC) (11mg, 0.07 mmol), diisopropylethylamine (16.4 μL, 0.09 mmol) at 25° C. for16 h. The solvents were evaporated, and the crude residue purified bysilica gel chromatography eluting with a gradient of dichloromethane,100% ethyl acetate, and 95% ethyl acetate/5% methanol to give the titlecompound (25 mg, 83%). ¹H NMR (300MHz, CDCl₃) δ ppm 0.79(s, 9H),1.47-1.39(m, 1H), 1.93-1.84(m, 1H), 2.25(s, 3H), 2.93-2.77(m, 2H),3.00-2.97(dd, J=7.72, 2.94 Hz, 2H), 3.72-3.60(m, 2H), 3.66(s, 3H),4.354.27(m, 1H), 4.45-4.39(m, 1H), 4.52(m, 1H), 5.28-5.26(d, J=8.46 Hz,1H), 5.91-5.89(d, J=8.46 Hz, 1H), 6.16-6.13(d, J=9.56 Hz, 1H),7.14-7.04(m, 3H), 7.25-7.18(m, 9H), 7.69-7.66(m, 1H), 7.78-7.72(m, 1H),7.93-7.90(d, J=8.09 Hz, 2H), 8.70-8.68(d, J=4.04 Hz, 1H).

EXAMPLE 160methyl(1S)-1-({[(1R,3S,4S)-4-{[(2S)-3,3-dimethyl-2-(2-oxoimidazolidin-1-yl)butanoyl]amino}-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamateEXAMPLE 160Atert-butyl(2S)-3,3-dimethyl-2-(2-oxoimidazolidin-1-yl)butanoate

To a solution containing the product from Example 6F (0.050 g, 0.22mmol) in toluene (4.0 mL) was added bis(4-nitrophenyl)carbonate (0.080g, 0.263 mmol), and the mixture was heated to 100° C. for 48 hours. Thereaction was cooled, diluted with ethyl acetate, and washed three timeswith 10% Na₂CO₃. The organic was washed with brine and dried over MgSO₄,filtered and evaporated. The residue was chromatographed on silica geleluting with a gradient starting with chloroform and ending with 50%ethyl acetate in chloroform to give the product (0.062 g).

EXAMPLE 160B (2S)-3,3-dimethyl-2-(2-oxoimidazolidin-1-yl)butanoic acid

To a solution containing the product from Example 160A (0.050 g, 0.195mmol) in dichloromethane (1.0 mL) was added trifluoracetic acid (1.0mL), and the mixture was stirred at room temperature for 2 hours. Thesolvent was evaporated and the residue was triturated with ether to givea white solid, which was collected by filtration and used withoutfurther purification.

EXAMPLE 160Cmethyl(1S)-1-({[(1R,3S,4S)-4-{[(2S)-3,3-dimethyl-2-(2-oxoimidazolidin-1-yl)butanoyl]amino}-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate

A solution of the product of Example 1H (0.020 g, 0.038 mmol) intetrahydrofuran (0.40 mL) was treated with the product from Example 160B(0.0075 g, 0.038 mmol), DEPBT (0.017 g, 0.057 mmol), andN,N-diisopropylethylamine (0.035 mL, 0.201 mmol), stirred at 25° C. for12 hours and partitioned between ethyl acetate and 10% Na₂CO₃ solution.The organic layer was washed with additional 10% Na₂CO₃ solution andbrine, dried over MgSO₄, filtered and concentrated. The residue waschromatographed on silica gel eluting with a gradient starting withdichloromethane and ending with 50% acetone in dichloromethane to givethe title compound (0.020 g, 74% yield). ¹H NMR (300 MHz, DMSO-d₆), δppm 0.80 (s, 9 H), 0.86 (s, 9 H), 1.33-1.56 (m, 2 H), 2.55-2.72 (m, 4H), 2.82 (dd, J=5.9, 12.9 Hz, 1 H), 2.89-2.56 (m, 1 H), 3.08 (q, J=8.8Hz, 1 H), 3.24-3.28 (m, 1 H), 3.50-3.57 (m, 4 H), 3.83 (d, J=9.6 Hz, 1H), 3.87-3.94 (m, 1 H), 3.97 (s, 1 H), 4.14-4.20 (m, 1H), 4.42 (d, J=7.4Hz, 1 H), 6.29 (s, 1 H), 6.88 (d, J=9.6 Hz, 1 H), 7.09-7.25 (m, 7 H),7.30-7.34 (m, 1 H), 7.44 (d, J=9.6 Hz, 1 H), 7.83-7.97 (m, 5 H), 8.62(m, 1 H).

EXAMPLE 161methyl(1S)-1-({[(1R,3S,4S)-3-hydroxy-4-{[(2S,3S)-3-methyl-2-(2-oxoimidazolidin-1-yl)pentanoyl]amino}-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamateEXAMPLE 161Atert-butyl(2S,3S)-3-methyl-2-(2-oxoimidazolidin-1-yl)pentanoate

To a solution containing the product from Example 3G (0.50 g, 2.08 mmol)in 1,2-dichloroethane (90.0 mL) was added bis(4nitrophenyl) carbonate(0.80 g, 2.63 mmol), and the mixture was heated to 70° C. for 12 hours.The reaction mixture was cooled and concentrated. The residue wasdissolved in ethyl acetate, and washed with 10% Na₂CO₃ (3×), brine,dried over MgSO₄, filtered and concentrated. The residue waschromatographed on silica gel eluting with a gradient starting withdichloromethane and ending ethyl acetate to give the product (0.49 g,88% yield).

EXAMPLE 161B (2S,3S)-3-methyl-2-(2-oxoimidazolidin-1-yl)pentanoic acid

To a solution containing the product from Example 161A (0.49 g, 1.91mmol) in tetrahydrofuran (10.0 mL) was added aqueous HCl solution (5.0mL, 4 N), and the mixture was stirred at 60° C. for 12 hours. Thesolvent was evaporated to give a white solid, which was used withoutfurther purification.

EXAMPLE 161Cmethyl(1S)-1-({[(1R,3S,4S)-3-hydroxy-4-{[(2S,3S)-3-methyl-2-(2-oxoimidazolidin-1-yl)pentanoyl]amino}-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate

A solution of the product of Example 1H (0.020 g, 0.038 mmol) intetrahydrofuran (0.40 mL) was treated with the product from Example 161B(0.0075 g, 0.038 mmol), DEPBT (0.017 g, 0.057 mmol), andN,N-diisopropylethylamine (0.035 mL, 0.201 mmol), stirred at 25° C. for12 hours and partitioned between ethyl acetate and 10% Na₂CO₃ solution.The organic layer was washed with additional 10% Na₂CO₃ solution andbrine, dried over MgSO₄, filtered and concentrated. The residue waschromatographed on silica gel eluting with a gradient starting withdichloromethane and ending with 50% acetone in dichloromethane to givethe title compound (0.019 g, 71% yield). ¹H NMR (300 MHz, DMSO-d₆), δppm 0.68 (d, J=6.6 Hz, 3 H), 0.75 (t, J=7.4 Hz, 3 H), 0.80 (s, 9 H),0.85-0.96 (m, 1H), 1.24-1.35 (m, 2H), 1.48-1.56 (m, 1 H), 1.70-1.79 (m,1 H), 2.54-2.72 (m, 3 H), 2.79-2.85 (m, 2H), 2.98-3.14 (m, 3H),3.50-5.58 (m, 4 H), 3.77-3.91 (m, 3 H), 4.11-4.23 (m, 1H), 4.54 (d,J=7.4 Hz, 1 H), 6.31 (s, 1 H), 6.90 (d, J=9.6 Hz, 1 H), 7.09-7.26 (m, 8H), 7.30-7.34 (m, 1 H), 7.80-7.97 (m, 5 H), 8.64 (m, 1 H).

EXAMPLE 162methyl(1S)-1-{1[((1S,2S,4S)4-{[3-(aminosulfonyl)benzoyl]amino}-1-benzyl-2-hydroxy-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamate

A solution of benzenesulfonamide-3-carboxylic acid (0.05 g, 0.25 mmol)and Example 23S (0.11 g, 0.24 mmol) in tetrahydrofuran (4 mL) wastreated with DEPBT (0.11 g, 0.37 mmol) and diisopropylethylamine (0.16g, 1.2 mmol) at 25° C. The mixture was stirred for 16 h and partitionedbetween 10% sodium carbonate and dichloromethane. The organic layer wasseparated, dried over sodium sulfate, and the solvents were evaporated.The crude residue was purified by chromatography on silica gel elutingwith 30% ethyl acetate in dichloromethane to give the title compound(0.09 g, 58% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm 1.68 (s, 9 H),2.77-3.02 (m, 5 H), 3.54 (s, 3 H), 3.84 (d, J=8.82 Hz, 2 H), 4.00-4.17(m, 2 H), 4.30-4.42 (m, 1 H), 5.30 (s, 1 H), 5.79 (s, 2 H), 6.57 (s, 1H), 7.04 (s, 1 H), 7.09-7.23 (m, 10 H), 7.43 (t, J=7.72 Hz, 1 H), 7.73(s, 1 H), 7.92 (d, J=7.35 Hz, 1 H), 8.19 (s, 1 H).

EXAMPLE 163methyl(1S)-1-({[(1S,3S,4S)-4-[(3-chloro-2-methylbenzoyl)amino]-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate

A solution of 3-chloro-2-methyl benzoic acid (8.4 mg, 0.49 mmol) inN,N-dimethylformamide (0.3 mL) was treated with Example 2C (25 mg, 0.047mmol), 1-hydroxybenzotriazole hydrate (HOBT) (7.6 mg, 0.056 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC) (11mg, 0.07 mmol), diisopropylethylamine (16.4 uL, 0.09 mmol) at 25° C. for16 h. The solvents were evaporated, and the crude residue purified bysilica gel chromatography eluting with a gradient of dichloromethane,100% ethyl acetate, and 95% ethyl acetate/5% methanol to give the titlecompound (17.7 mg, 55%). ¹H NMR (300 MHz, CDCl₃) δ ppm 0.92(s, 9H),1.89-1.72(m, 2H), 2.20(s, 3H), 2.98-2.80(m, 4H), 3.60(s, 3H),3.79-3.74(m, 2H), 4.05(m, 1H), 4.28-4.20(m, 2H), 5.29(m, 1H),6.07-6.04(d, J=9.19 Hz, 1H), 6.22-6.20(d, J=7.72 Hz, 1H), 6.88(m, 1H),7.02-6.97(t, J=7.72 Hz, 1H), 7.32-7.16(m, 9H), 7.68-7.65(m, 1H),7.77-7.71(m, 1H), 7.89-7.87(d, J=8.09 Hz, 2H), 8.68(m, 1H).

EXAMPLE 164methyl(1S)-1-({[(1S,3S,4S)-3-hydroxy-4-[(3-hydroxy-2-methylbenzoyl)amino]-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate

A solution of 3-hydroxy-2-methyl benzoic acid (7.5 mg, 0.49 mmol) inN,N-dimethylformamide (0.3 mL) was treated with Example 2C (25 mg, 0.047mmol), 1-hydroxybenzotriazole hydrate (HOBT) (7.6 mg, 0.056 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC) (11mg, 0.07 mmol), diisopropylethylamine (16.4 μL, 0.09 mmol) at 25° C. for16 h. The solvents were evaporated, and the crude residue purified bysilica gel chromatography eluting with a gradient of dichloromethane,100% ethyl acetate, and 95% ethyl acetate/5% methanol to give the titlecompound (24.8 mg, 79%). ¹H NMR (300 MHz, CD₃OD) δ ppm 0.89(s, 9H),1.86-1.77(m, 2H), 1.91(s, 3H), 2.77-2.70(m, 1H), 2.94-2.92(m, 3H),3.53(s, 3H), 3.85(m, 2H), 4.53-4.48(m, 2H), 6.48-6.45(d, J=6.62 Hz, 1H),6.73-6.71(d, J=7.35 Hz, 1H), 6.90-6.85(t, J=7.72 Hz, 1H), 7.35-7.18(m,8H), 7.80-7.75(m, 3H), 7.89-7.84(m, 1H), 8.57(m, 1H).

EXAMPLE 165methyl(1S)-1-({[(1S,3S,4S)-3-hydroxy-4-{[(3-methylisoxazol-4-yl)carbonyl]amino}-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate

A solution of 3-methyl-4-carboxyl isoxazole (6.3 mg, 0.49 mmol) inN,N-dimethylformamide (0.3 mL) was treated with Example 2C (25 mg, 0.047mmol), 1-hydroxybenzotriazole hydrate (HOBT) (7.6 mg, 0.056 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC) (11mg, 0.07 mmol), diisopropylethylamine (16.4 μL, 0.09 mmol) at 25° C. for16 h. The solvents were evaporated, and the crude residue purified bysilica gel chromatography eluting with a gradient of dichloromethane,100% ethyl acetate, and 95% ethyl acetate/5% methanol to give the titlecompound (24 mg, 80%). ¹H NMR (300 MHz, CDCl₃-D6) δ ppm 0.89(s, 9H),1.75-1.64(m, 2H), 2.39(s, 3H), 2.94-2.79(m, 4H), 3.60(s, 3H),3.76-3.70(m, 2H), 4.21-4.07(m, 2H), 4.29(d, J=4.78 Hz, 1H), 5.25-5.22(d,J=8.46 Hz, 1H), 6.16-6.13(d, J=7.72 Hz, 1H), 6.31-6.28(d, J=8.82 Hz,1H), 7.25-7.15(m, 8H), 7.68-7.65(m, 1H), 7.78-7.73(m, 1H), 7.87-7.84(d,J=8.46 Hz, 2H), 8.60(s, 1H), 8.68-8.66(m, 1H).

EXAMPLE 166methyl(1S)-1-({[(1S,3S,4S)-4-{[(3,5-dimethylisoxazol-4-yl)carbonyl]amino}-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate

A solution of 3,5-dimethyl isoxazole 4-carboxylic acid (6.9 mg, 0.49mmol) in N,N-dimethylformamide (0.3 mL) was treated with Example 2C (25mg, 0.047 mmol), 1-hydroxybenzotriazole hydrate (HOBT) (7.6 mg, 0.056mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(EDAC) (11 mg, 0.07 mmol), diisopropylethylamine (16.4 μL, 0.09 mmol) at25° C. for 16 h. The solvents were evaporated, and the crude residue waspurified by silica gel chromatography eluting with a gradient ofdichloromethane, 100% ethyl acetate, and 95% ethyl acetate/5% methanolto give the title compound (13 mg, 42%). ¹H NMR (300 MHz, CDCl₃) δ ppm0.90(s, 9H), 1.77-1.63(m, 2H), 2.27(s, 3H), 2.45(s, 3H), 3.02-2.75(m,4H), 3.60(s, 3H), 3.77-3.70(m, 2H), 4.20-4.1 1(m, 2H), 4.23-4.22(d,J=4.04 Hz, 1H), 5.25-5.22(d, J=8.82 Hz, 1H), 6.00-5.97(d, J=8.82 Hz,1H), 6.13-6.11(d, J=6.99 Hz, 1H), 7.25-7.13(m, 8H), 7.68-7.66(m, 1H),7.78-7.73(m, 1H), 7.87-7.84(d, J=8.09 Hz, 2H), 8.68(m, 1H).

EXAMPLE 167methyl(1S,4S,5S,7S,10S)-4benzyl-10-tert-butyl-5-hydroxy-1-isobutyl-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamateEXAMPLE 167AN¹-[(1S,2S,4S)-1-benzyl-2-hydroxy-4-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-5-(4-pyridin-2-ylphenyl)pentyl]-N²-[(benzyloxy)carbonyl]-L-leucinamide

A solution of N-[(benzyloxy)carbonyl]-L-leucine (22 μL, 0.083 mmol) inN,N-dimethylformamide (0.4 mL) was treated with Example 2C (40 mg, 0.075mmol), 1-hydroxybenzotriazole hydrate (HOBT) (12.2 mg, 0.09 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC) (17.5mg, 0.112 mmol), diisopropylethylamine (26 μL, 0.15 mmol) at 25° C. for16 h. The solvents were evaporated, and the crude residue purified bysilica gel chromatography eluting with a gradient starting withdichloromethane and ending with 100% ethyl acetate to give the titlecompound (45.6 mg, 78%).

EXAMPLE 167BN¹-[(1S,2S,4S)-1-benzyl-2-hydroxy-4-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-5-(4-pyridin-2-ylphenyl)pentyl]-L-leucinamide

A solution of Example 167A (40 mg, 0.051 mmol) in ethyl acetate (0.25mL) and methanol (0.25 mL) was treated with 1N HCl in dioxane, ahydrogen balloon, and 10% Pd/C (11 mg, 0.01 mmol) at 25° C. for 16h. Themixture was filtered, rinsed with methanol, and the solvents wereevaporated to give the title compound (33 mg, 100%).

EXAMPLE 167Cmethyl(1S,4S,5S,7S,10S)-4benzyl-10-tert-butyl-5-hydroxy-1-isobutyl-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate

A solution of Example 167B (11.2 mg, 0.017 mmol) in dichloromethane(0.25 mL) was treated with methyl chloroformate (2 μL, 0.026 mmol), andtriethylamine (4.8 μL, 0.034 mmol) at 25° C. for 1 h. The solvents wereevaporated, and the crude residue was purified by silica gelchromatography eluting with a gradient of dichloromethane, 100% ethylacetate, and 95% ethyl acetate/7% methanol to give the title compound (7mg, 57%). ¹H NMR (300 MHz, CDCl₃)δ ppm 0.87-0.84(s, 15H), 1.34-1.29(m,2H), 1.65-1.51(m, 3H), 2.67-2.60(m, 2H), 2.86-2.83(d, J=7.72 Hz, 2H),2.95-2.87(m, 1H), 3.52(s, 3H), 3.65(s, 3H), 3.78-3.73(m, 1H), 3.81(s,1H), 4.08-4.03(m, 1H), 4.24-4.19(m, 1H), 4.33(m, 1H), 7.17-7.12(m, 1H),7.26-7.20(m, H), 7.29-7.26(d, J=8.46 Hz, 2H), 7.35-7.30(m, 1H),7.81-7.77(m, 3H), 7.90-7.84(m, 1H).

EXAMPLE 168methyl(1S,4S,5S,7S,10S)-1-(2-amino-2-oxoethyl)-4-benzyl-10-tert-butyl-5-hydroxy-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate EXAMPLE 168AN¹-[(1S,2S,4S)-1-benzyl-2-hydroxy-4-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-5-(4-pyridin-2-ylphenyl)pentyl]-N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-N⁴-trityl-L-aspartamide

A solution ofN²-[(9H-fluoren-9-ylmethoxy)carbonyl]-N⁴-trityl-L-asparagine (47 μL,0.079 mmol) in N,N-dimethylformamide (0.3 mL) was treated with Example2C (40 mg, 0.075 mmol), 1-hydroxybenzotriazole hydrate (HOBT) (12.2 mg,0.09 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(EDAC) (17.5 mg, 0.112 mmol), diisopropylethylamine (26 μL, 0.15 mmol)at 25° C. for 16 h. The solvents were evaporated, and the crude residuepurified by silica gel chromatography eluting with a gradient startingwith dichloromethane and ending with 100% ethyl acetate to give thetitle compound (45 mg, 59%).

EXAMPLE 168BN¹-[(1S,2S,4S)-1-benzyl-2-hydroxy-4-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-5-(4-pyridin-2-ylphenyl)pentyl]-N⁴-trityl-L-aspartamide

A solution of Example 168A (45 mg, 0.04 mmol) in N,N-dimethylformamide(0.4 mL) was treated with piperidine (80 μL) at 25° C. for 16 h. Thesolvents were evaporated to give the crude title compound which was useddirectly in the next step.

EXAMPLE 168CN¹-[(1S,2S,4S)-1-benzyl-2-hydroxy-4-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-5-(4-pyridin-2-ylphenyl)pentyl]-N²-(methoxycarbonyl)-N⁴-trityl-L-aspartamide

A solution of Example 168B (24 mg, 0.027 mmol) in dioxane (0.25 mL) wastreated with methyl chloroformate (3.2 μL, 0.041 mmol) and triethylamine(7.5 μL, 0.054 mmol) at 25° C. for 0.5 h. The solvents were evaporatedto give the crude title compound (27.7 mg, 100%).

EXAMPLE 168Dmethyl(1S,4S,5S,7S,10S)-1-(2-amino-2-oxoethyl)-4-benzyl-10-tert-butyl-5-hydroxy-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate

A solution of Example 168C (27.7 mg, 0.027 mmol) in dichloromethane (0.5mL) was treated with trifluoroacetic acid (0.25 mL) at 25° C. for 2 h.The solvents were evaporated, and the residue was dissolved indichloromethane, washed with saturated sodium bicarbonate, dried overMgSO₄, filtered, and the solvents were evaporated. The crude residue waspurified by silica gel chromatography eluting with a gradient ofdichloromethane, 100% ethyl acetate, and 95% ethyl acetate/7% methanolto give the title compound (4 mg, 16%). ¹H NMR (300 MHz, DMSO-d₆) δ ppm0.81(s, 9H), 1.53(m, 2H), 2.42-2.30(m, 2H), 2.64-2.60(m, 1H),2.79-2.71(m, 4H), 3.50(s, 3H), 3.54(s, 3H), 3.61(m, 1H), 3.79(d, J=4.04Hz, 1H), 4.03(m, 4.13(m, 1H), 4.27(m, 1H), 4.57(bs, 1H), 6.17(m, 1H),6.84(m, 1H), 7.12(m, 1H), 7.21-7.19(m, 7H), 7.27(m, 1H), 7.48(d, J=7.81Hz, 1H), 7.82(bs, 2H), 7.87-7.86(d, J=7.81 Hz, 2H), 8.62-8.61(d, J=4.39Hz, 1H).

EXAMPLE 169 methyl2-{[(1S,2S,4S)-1-benzyl-2-hydroxy-4-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-5-(4-pyridin-2-ylphenyl)pentyl]amino}-1-[(methoxycarbonyl)amino]-2-oxoethylcarbamateEXAMPLE 169A bis[(methoxycarbonyl)amino]acetic acid

Methyl carbamate (1.0 g, 13.3 mmol) and glyoxylic acid monohydrate (0.63g, 6.7 mmol) were combined in chloroform (7 mL). Naphthalene sulfonicacid (13 mg, 0.06 mmol) was added and the mixture was heated at refluxfor 6 hours. The solution was then filtered and the white solid wascollected and dried to yield 1.4 g, 51%:

EXAMPLE 169B methyl2-{[(1S,2S,4S)-1-benzyl-2-hydroxy-4-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-5-(4-pyridin-2-ylphenyl)pentyl]amino}-1-[(methoxycarbonyl)amino]-2-oxoethylcarbamate

The product from Example 169A (13.2 mg, 0.06 mmol) was dissolved inN,N-dimethylformamide (0.25 mL) and N-hydroxybenzotriazole (13 mg, 0.10mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (18.4 mg, 0.10mmol) were added followed by the product from Example 2C (34.2 mg, 0.06mmol). Triethylamine (9 uL, 0.06 mmol) was added and the mixture wasstirred at ambient temperature for 18 hours. The solution wasconcentrated and the crude residue was purified on a 2 mm preparativesilica gel TLC plate (5% CH₃OH/CHCl₃) to give an amorphous solid (38.4mg, 83%). ¹H NMR (CDCl₁) δ 8.65 (d, 1H), 7.86 (d, 2H), 7.78-7.60 (m,2H), 7.27-7.11 (m, 9H), 6.94-6.70 (br s, 1H), 6.36-6.24 (br s, 1H),6.24-6.04 (br d, 1H), 6.02-5.84 (br d, 1H), 5.41-5.25 (m, 2H), 4.23-4.10(m, 1H), 4.10-3.95 (q, 1H), 3.75 (d, 1H), 3.67 (s, 3H), 3.66 (s, 3H),3.63 (s, 3H), 2.98-2.8 (m, 3H), 2.8-2.65 (m, 1H), 0.91 (s, 9H).

EXAMPLE 170methyl(1S,4S,6S,7S,10S)-7-benzyl-1,10-di-tert-butyl-6-hydroxy-2,9,12,14-tetraoxo-4-(4-pyridin-2-ylbenzyl)-15-oxa-3,8,11,13-tetraazahexadec-1-ylcarbamate

A solution of Example 58C (11.8 mg, 0.0183 mmol) in dioxane (0.2 mL) wastreated with methyl isocyanoformate (2.2 μL, 0.027 mmol) andtriethylamine (5.1 μL, 0.0365 mmol) at 25° C. for 1 h. The solvents wereevaporated and the crude residue was purified by silica gelchromatography using dichloromethane to 100% ethyl acetate to 95% ethylacetate/5% methanol to give the title compound (9 mg, 66%). ¹H NMR (300MHz, CD₃OD) δ ppm 0.86(s, 9H), 0.92(s, 9H), 1.71-1.65(m, 2H),2.67-2.60(m, 1H), 2.86-2.81(m, 2H), 2.98-2.92(m, 1H), 3.52(s, 3H),3.76(s, 3H), 3.82-3.79(d, J=6.99 Hz, 2H), 4.08(m, 1H), 4.19(m, 1H),4.33(m, 1H), 7.11-7.06(m, 1H), 7.33-7.16(m, 6H), 7.73-7.70(d, J=9.19 Hz,1H), 7.81-7.77(m, 3H), 7.90-7.84(m, 1H), 8.56(d, J=4.04 Hz, 1H).

EXAMPLE 171methyl(1S,4S,6S,7S,10S)-7-benzyl-1,10-di-tert-butyl-6-hydroxy-14,14-dimethyl-2,9,12,15-tetraoxo-4-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazahexadec-1-ylcarbamate

A solution of Example 58C (11.2 mg, 0.0173 mmol) in dioxane (0.2 mL) wastreated with 1-chlorocarbonyl-1-methyl ethyl acetate (3.8 μL, 0.0259mmol) and triethylamine (4.8 uL, 0.0345 mmol) at 25° C. for 1 h. Thesolvents were evaporated, and the crude residue was purified by silicagel chromatography using dichloromethane to 100% ethyl acetate to 95%ethyl acetate/5% methanol to give the title compound (11 mg, 82%). ¹HNMR (300 MHz, CDCl₃) δ ppm 0.90(s, 9H), 0.92(s, 9H), 1.61(s, 3H),1.67(s, 3H), 1.67-1.61(m, 2H), 2.10(s, 3H), 2.96-2.77(m, 4H), 3.62(s,3H), 3.60(m, 1H), 3.74(m, 2H), 4.02(m, 1H), 4.06-4.03(d, J=8.46 Hz, 1H),4.24-4.17(m, 1H), 5.36-5.33(d, J=9.19 Hz, 1H), 6.16-6.14(d, J=7.72 Hz,1H), 6.25-6.22(d, J=8.82 Hz, 1H), 6.43-6.41(d, J=8.09 Hz, 1H),7.23-7.13(m, 8H), 7.77-7.68(m, 2H), 7.88-7.85(d, J=8.09 Hz, 2H),8.68-8.66(d, J=4.78 Hz, 1H).

EXAMPLE 172(4S,7S,8S,10S,13S)-7-benzyl-4,13-di-tert-butyl-8-hydroxy-2,5,12,15-tetraoxo-10-(4-pyridin-2-ylbenzyl)-16-oxa-3,6,11,14-tetraazaheptadec-1-ylacetate

A solution of Example 58C (34 mg, 0.0526 mmol) in dioxane (0.2 mL) wastreated with acetoxy acetyl chloride (8.5 μL, 0.079 mmol) andtriethylamine (14.6 μL, 0.105 mmol) at 25° C. for 1 h. The solvents wereevaporated, and the crude residue was purified by silica gelchromatography using dichloromethane to 100% ethyl acetate to 95% ethylacetate/5% methanol to give the title compound (30 mg, 77%). ¹H NMR (300MHz, CDCl₃) δ ppm 0.92(s, 18H), 1.66-1.61(m, 2H), 2.16(m, 1H), 2.17(s,3H), 2.88-2.77(m, 4H), 3.62(s, 3H), 3.70-3.66(m, 1H), 3.78-3.75(d,J=8.82 Hz, 1H), 4.06-3.97(m, 1H), 4.22-4.19(m, 2H), 4.62-4.47(m, 2H),5.43-5.40(d, J=9.19 Hz, 1H), 6.21-6.18(d, J=7.72 Hz, 1H), 6.40-6.37(d,J=9.19 Hz, 1H), 6.71-6.68(d, J=9.19 Hz, 1H), 7.24-7.13(m, 8H),7.79-7.67(m, 2H), 7.86-7.83(m, 2H), 8.70(m, 1H).

EXAMPLE 173methyl(1S)-1-({[(1S,3S,4S)-4-{[(2S)-2-(glycoloylamino)-3,3-dimethylbutanoyl]amino}-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate

A solution of Example 58C (22 mg, 0.029 mmol) in methanol (0.15 mL) andtetrahydrofuran (0.15 mL) was treated with potassium carbonate (12.2 mg,0.082 mmol) at 25° C. for 1 h. The solvents were evaporated, and thecrude residue was purified by silica gel chromatography eluting with agradient of dichloromethane, 100% ethyl acetate, and 95% ethylacetate/7% methanol to give the title compound (16 mg, 78%). ¹H NMR (300MHz, CDCl₃) δ ppm 0.88(s, 9H), 0.93(s, 9H), 1.56(m, 2H), 2.97-2.74(m,4H), 3.58(m, 1H), 3.67(s, 3H), 3.94-3.78(m, 4H), 4.08(m, 1H),4.22-4.19(d, J=9.56 Hz, 1H), 4.55-4.53(d, J=6.25 Hz, 1H), 5.44-5.41(d,J=9.19 Hz, 1H), 6.82-6.80(d, J=6.25 Hz, 1H), 7.30-7.11(m, 11H),7.70-7.63(m, 3H), 7.81-7.75(m, 1H), 8.65-8.64(d, J=4.05 Hz, 1H).

EXAMPLE 174(3S,6S,7S,9S,12S)-6-benzyl-3[(tert-butoxycarbonyl)amino]-12-tert-butyl-7-hydroxy-2,2-dimethyl-4,11,14trioxo-9-(4pyridin-2-ylbenzyl)-15-oxa-5,10,13-triazahexadec-1-ylacetate EXAMPLE 174A (3R)-4,4dimethyl-2-oxotetrahydrofuran-3-yltrifluoromethanesulfonate

To a solution containing R-(−)-pantolactone (12.0 g, 92.31 mmol) indichloromethane (125.0 mL) was added pyridine (9.2 mL, 118.92 mmol), andthe mixture was cooled to −78° C. and triflic anhydride (17.0 mL, 101.05mmol) was added dropwise. The mixture was stirred at −78° C. for 30minutes and then at room temperature for 1 hour. The reaction wasevaporated and the residue was dissolved in ether, and washed with 5%KHSO₄. The organic was washed with brine and dried over MgSO₄, filteredand evaporated to give the crude product (23.71 g), which was usedwithout further purification.

EXAMPLE 174B (3S)-3-azido-4,4-dimethyldihydrofuran-2(3H)-one

To a solution containing the product from Example 174A (4.6 g, 17.56mmol) in toluene (80.0 mL) was added tetra-n-butylammonium azide (5.0 g,17.57 mmol) at room temperature, and the mixture was stirred for 5hours. The reaction was diluted with ether and washed with water, diluteNaHCO₃, 10% citric acid and brine. The organic layer was dried overMgSO₄, filtered and concentrated to give the crude product, which wasused without further purification (2.79 g).

EXAMPLE 174C Add Name

To a solution of the product of Example 174B (4.58 g, 29.55 mmol) inmethanol (100.0 mL) was added 10% Pd on carbon (1.5 g), and the reactionwas stirred under an atmosphere of hydrogen (balloon pressure) for 12hours. The mixture was filtered through celite and the solvent wasevaporated. The residue was dissolved in tetrahydrofuran (150.0 mL) andtriethylamine (12.0 mL, 86.10 mmol) and di-tert-butyl dicarbonate (7.0g, 32.07 mmol) were added and the mixture was stirred at roomtemperature for 12 hours. The solvent was evaporated and the residue wasdissolved in ethyl acetate and the organic layer was washed with 10%citric acid, dilute NaHCO₃, and brine, dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting witha gradient starting with dichloromethane and ending with 10% ethylacetate in dichloromethane to give the title compound (4.2 g, 62%yield).

EXAMPLE 174D benzylN-(tert-butoxycarbonyl)-4-hydroxy-3-methyl-L-valinate

To a solution of the product of Example 174C (0.20 g, 0.872 mmol) indioxane (1.5 mL) was added a solution of potassium hydroxide (0.050 g,0.891 mmol) in water (1.5 ml) at room temperature, and the mixture wasstirred for 60 hours. The solvent was evaporated and toluene was addedand evaporated twice to give a white solid. The solid was dissolved inN,N-dimethylformamide (4.0 mL) and benzyl bromide (0.10 mL, 0.841 mmol)was added and the mixture was stirred at room temperature for 12 hours.The reaction was extracted with ethyl acetate and the organic layer waswashed with water and brine, dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel eluting witha gradient starting with hexanes and ending with 40% ethyl acetate inhexanes to give the title compound (0.196 g, 67% yield).

EXAMPLE 174E 4-(acetyloxy)-N-(tert-butoxycarbonyl)-3-methyl-L-valine

To a solution of the product of Example 174D (0.175 g, 0.519 mmol) indichloromethane (5.0 mL) were added 4-(dimethylamino)pyridine (0.070 g,0.573 mmol) and acetic anhydride (0.054 mL, 0.571 mmol) and the mixturewas stirred at room temperature for 30 minutes. The reaction wasextracted with ethyl acetate and the organic layer was washed with 10%citric acid, dilute NaHCO₃, and brine, dried over MgSO₄, filtered andconcentrated. The residue was dissolved in a mixture of ethyl acetate(4.0 mL) and methanol (1.0 mL) and 20% Pd(OH)₂ on carbon (0.10 g) wasadded, and the reaction was stirred under an atmosphere of hydrogen(balloon pressure) for 1 hour. The mixture was filtered through celiteand the solvent was evaporated to give the title compound (0.15 g),which was used without further purification.

EXAMPLE 174F(3S,6S,7S,9S,12S)-6-benzyl-3-[(tert-butoxycarbonyl)amino]-12-tert-butyl-7-hydroxy-2,2-dimethyl-4,11,14-trioxo-9-(4-pyridin-2-ylbenzyl)-15-oxa-5,10,13-triazahexadec-1-ylacetate

To a solution of the product of Example 2C (0.275 g, 0.517 mmol) intetrahydrofuran (0.40 mL) were added the product from Example 174E (0.15g, 0.519 mmol), DEPBT (0.233 g, 0.779 mmol), andN,N-diisopropylethylamine (0.45 mL, 2.58 mmol), and the mixture wasstirred at room temperature for 2 hours. The reaction was partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic layer waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was chromatographed on silica geleluting with a gradient starting with dichloromethane and ending withethyl acetate to give the title compound (0.214 g, 50% yield). ¹H NMR(300 MHz, DMSO-d₆), δ ppm 0.80 (m, 15 H), 1.39 (s, 9 H), 1.47-1.56 (m, 2H), 1.99 (s, 3 H), 2.72-2.79 (m, 3 H), 3.49 (s, 3 H), 3.62-3.65 (m, 2H), 3.80-3.84 (m, 2 H), 4.05 (d, J=9.9 Hz, 1 H), 4.10-4.24 (m, 2 H),4.94 (d, J=4.8 Hz, 1 H), 6.60-6.65 (m, 2 H), 7.10-7.21 (m, 8 H),7.29-7.31 (m, 1 H), 7.52 (d, J=8.8 Hz, 1 H), 7.77 (d, J=8.5 Hz, 1 H),7.82-7.89 (m, 4 H), 8.64 (m, 1 H).

EXAMPLE 175methyl(1S,4S,5S,7S,10S)-4benzyl-10-tert-butyl-5-hydroxy-1-(2-hydroxy-1,1-dimethylethyl)-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamateEXAMPLE 175AN¹-[(1S,3S,4S)-4-({(2S)-2-[(tert-butoxycarbonyl)amino]-4-hydroxy-3,3-dimethylbutanoyl}amino)-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]-N²-(methoxycarbonyl)-3-methyl-L-valinamide

A solution of the product of Example 174F (0.020 g, 0.025 mmol) in amixture of dioxane (0.250 mL) and water (0.100 mL) was added an aqueoussolution of lithium hydroxide (0.028 mL, 1 N), and the mixture wasstirred at room temperature for 1 hour. The reaction was diluted withethyl acetate and washed with brine, dried over MgSO₄, filtered andconcentrated to give the title compound, which was used without furtherpurification.

EXAMPLE 175Bmethyl(1S,4S,5S,7S,10S)-4benzyl-10-tert-butyl-5-hydroxy-1-(2-hydroxy-1,1-dimethylethyl)-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate

To a solution of the product of Example 175A (0.025 mmol) indichloromethane (1.0 mL) was added trifluoroacetic acid (1.0 mL), andthe mixture was stirred at room temperature for 1 hour. The solvent wasevaporated, and the reaction mixture was partitioned between ethylacetate and dilute NaHCO₃ solution. The organic layer was washed withbrine, dried over MgSO₄, filtered and concentrated. The residue wasdissolved in tetrahydrofuran (0.25 mL) and diisopropylethylamine (0.015mL, 0.086 mmol) and methyl chloroformate (0.002 mL, 0.026 mmol) wereadded at room temperature. After 2 hours water was added and thereaction was extracted with ethyl acetate. The organic layer was washedwith brine, dried over MgSO₄, filtered and concentrated. The residue waschromatographed on silica gel eluting with a gradient starting withdichloromethane and ending with ethyl acetate to give the title compound(0.006 g, 34% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.76 (2s, 6 H),0.79 (s, 9 H), 1.45-1.56 (m, 2 H), 2.71-2.80 (m, 3 H), 3.08 (dd, J=5.4,10.9 Hz, 1 H), 3.18 (dd, J=5.4, 10.9 Hz, 1 H), 3.49 (s, 3 H), 3.55 (s, 3H), 3.59-3.67 (m, 1 H), 3.81 (d, J=9.6 Hz, 1 H), 4.02 (d, J=9.2 Hz, 1H), 4.04-4.21 (m, 2 H), 4.62 (m, 1 H), 4.90 (d, J=5.5 Hz, 1 H), 6.61 (d,J=9.6 Hz, 1 H), 6.92 (d, J=9.2 Hz, 1 H), 7.10-7.21 (m, 7 H), 7.29-7.31(m, 1 H), 7.47 (d, J=8.8 Hz, 1 H), 7.78 (d, J=8.8 Hz, 1 H), 7.82-7.89(m, 4 H), 8.64 (m, 1 H).

EXAMPLE 176methyl(1S,4S,5S,7S,10)-1-{[(aminocarbonyl)amino]methyl}-4-benzyl-10-tert-butyl-5-hydroxy-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamateEXAMPLE 176A 3-[(aminocarbonyl)amino]-N-(methoxycarbonyl)-L-alanine

A solution of 2-amino-3-ureido-propionic acid (0.147 g, 1.0 mmol) in1,4-dioxane (1.0 mL) and 1 N NaOH (3.6 mL) was treated with methylchloroformate (0.153 mL, 2.0 mmol), stirred at 60° C. for 7 hours, andextracted with dichloromethane. The aqueous phase was acidified to pH 7with 1 N HCl and evaporated to dryness. The resulting solid wastrituated with 3:1 dichloromethane/isopropanol, filtered, and thefiltrate was concentrated to yield a white solid (0.11 g, 53.6%) whichwas used for the next step without further purification.

EXAMPLE 176Bmethyl(1S,4S,5S,7S,10S)-1-{[(aminocarbonyl)amino]methyl}-4-benzyl-10-tert-butyl-5-hydroxy-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate

A solution containing the product from Example 2C (0.025 g, 0.047 mmol)in tetrahydrofuran (0.5 mL) was treated with the product from Example176A (0.014 g, 0.07 mmol), DEPBT (0.028 g, 0.094 mmol), andtriethylamine (0.016 mL, 0.117 mmol), stirred at 25° C. for 7 hours, andpartitioned between ethyl acetate and 10% NaHCO₃ solution. The organicphase was washed with additional 10% NaHCO₃ solution and brine, driedover MgSO₄, filtered and concentrated. The product was purified bychromatography on silica gel eluting with 7% methanol/dichloromethane togive the title compound (0.019 g, 55% yield). ¹H NMR (300 MHz, DMSO-d₆)δ ppm 0.79 (s, 9H), 1.33-1.60 (m, 2H), 2.63-2.86 (m, 4H), 2.99-3.28 (m,2H), 3.49 (s, 3H), 3.55 (s, 3H), 3.81 (d, J=9.56 Hz, 1H), 3.89-4.22 (m,3H), 4.89 (d, J=6.62 Hz, 1H), 5.63 (s, 2H), 5.97 (s, 1H), 6.61 (d, 1H),7.09-7.37 (m, 9H), 7.49 (d, J=9.19 Hz, 1H), 7.69-7.96 (m, 5H), 8.63 (d,J=4.41 Hz, 1H).

EXAMPLE 177methyl(1S,4S,5S,7S,10S)-4benzyl-10-tert-butyl-5-hydroxy-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-1-(pyridin-2-ylmethyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamateEXAMPLE 177A N-(methoxycarbonyl)-3-pyridin-2-yl-L-alanine

A solution of 2-amino-3-pyridin-2-yl-propionic acid (0.168 g, 1.0 mmol)in 1,4-dioxane (1.0 mL) and 1 N NaOH (3.6 mL) was treated with methylchloroformate (0.153 mL, 2.0 mmol), stirred at 60° C. for 7 hours, andextracted with dichloromethane. The aqueous phase was acidified to pH 7with 1 N HCl and evaporated to dryness. The resulting solid wastrituated with 3:1 dichloromethane/isopropanol, filtered, and thefiltrate was concentrated to yield a yellow solid (0.146 g, 65%) whichwas used for the next step without further purification.

EXAMPLE 177Bmethyl(1S,4S,5S,7S,10S)-4benzyl-10-tert-butyl-5-hydroxy-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-1-(pyridin-2-ylmethyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate

A solution containing the product from Example 2C (0.025 g, 0.047 mmol)in tetrahydrofuran (0.5 mL) was treated with the product from Example177B (0.016 g, 0.07 mmol), DEPBT (0.028 g, 0.094 mmol), andtriethylamine (0.016 mL, 0.1 17 mmol), stirred at 25° C. for 7 hours,and partitioned between ethyl acetate and 10% NaHCO₃ solution. Theorganic phase was washed with additional 10% NaHCO₃ solution and brine,dried over MgSO₄, filtered and concentrated. The product was purified bychromatography on silica gel eluting with 7% methanol/dichloromethane togive the title compound (0.02 g, 58% yield). ¹H NMR (300 MHz, DMSO-d₆) δppm 0.79 (s, 9H), 1.35-1.56 (m, 2H), 2.52-2.66 (m, 2H), 2.66-2.88 (m,4H), 3.43 (s, 3H), 3.48 (s, 3H), 3.59-3.70 (m, 1H), 3.82 (d, J=9.93 Hz,1H), 3.99-4.29 (m, 3H), 4.95 (d, J=5.52 Hz, 1H), 6.65 (d, J=10.66 Hz,1H), 7.09-7.38 (m, 10H), 7.59 (d, J=7.72 Hz, 1H), 7.69 (d, J=9.19 Hz,1H), 7.76-7.87 (m, 4H), 7.89 (d, J=8.46 Hz, 2H), 8.37 (d, J=4.78 Hz,1H), 8.41 (s, 1H), 8.61 (d, J=4.78 Hz, 1H).

EXAMPLE 178methyl(1S,4S,5S,7S,10S)-4benzyl-10-tert-butyl-5-hydroxy-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-1-(1,3-thiazol-4-ylmethyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamateEXAMPLE 178A N-(methoxycarbonyl)-3-(1,3-thiazol-4-yl)-L-alanine

A solution of 2-amino-3-thiazol-2-yl-propionic acid (0.172 g, 1.0 mmol)in 1,4dioxane (1.0 mL) and 1 N NaOH (3.6 mL) was treated with methylchloroformate (0.153 mL, 2.0 mmol), stirred at 60° C. for 7 hours, andextracted with dichloromethane. The aqueous phase was acidified to pH 7with 1 N HCl and evaporated to dryness. The resulting solid wastrituated with 3:1 dichloromethane/isopropanol, filtered, and thefiltrate was concentrated to yield a white solid (0.155 g, 67%) whichwas used for the next step without further purification.

EXAMPLE 178Bmethyl(1S,4S,5S,7S,10S)-4benzyl-10-tert-butyl-5-hydroxy-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-1-(1,3-thiazol-4-ylmethyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate

A solution containing the product from Example 2C (0.025 g, 0.047 mmol)in tetrahydrofuran (0.5 mL) was treated with the product from Example178B (0.016 g, 0.07 mmol), DEPBT (0.028 g, 0.094 mmol), andtriethylamine (0.016 mL, 0.117 mmol), stirred at 25° C. for 7 hours, andpartitioned between ethyl acetate and 10% NaHCO₃ solution. The organicphase was washed with additional 10% NaHCO₃ solution and brine, driedover MgSO₄, filtered and concentrated. The product was purified bychromatography on silica gel eluting with 7% methanol/dichloromethane togive the title compound (0.019 g, 54% yield). ¹H NMR (300 MHz, DMSO-d₆)δ ppm 0.79 (s, 9H), 1.32-1.56 (m, 2H), 2.64-2.77 (m, 3H), 2.78-3.04 (m,2H), 3.49 (s, 6H,) 3.56-3.67 (m, 1H), 3.82 (d, J=10.30 Hz, 1H),4.01-4.17 (m, 2H), 4.29-4.43 (m, 1H), 4.91 (d, J=5.52 Hz, 1H,) 6.65 (d,1H), 7.07-7.41 (m, 11H), 7.55 (d, 1H), 7.73-7.94 (m, 6H), 8.62 (d,J=4.41 Hz, 1H), 8.99 (d, J=1.84 Hz, 1H).

EXAMPLE 179(3S,6S,7S,9S,12S)-6-benzyl-12-tert-butyl-7-hydroxy-3-[(methoxycarbonyl)amino]-2,2-dimethyl-4,11,14-trioxo-9-(4-pyridin-2-ylbenzyl)-15-oxa-5,10,13-triazahexadec-1-ylacetate

To a solution of the product of Example 174F (0.030 g, 0.037 mmol) indioxane (0.50 mL) at 0° C. was added a solution of HCl in dioxane (3.0mL, 4 N), and the mixture was stirred at room temperature for 1 hour.The solvent was evaporated, and the residue was dissolved intetrahydrofuran (0.40 mL) and diisopropylethylamine (0.030 mL, 0.172mmol) and methyl chloroformate (0.0032 mL, 0.041 mmol) were added atroom temperature. After 1 hour water was added and the reaction wasextracted with ethyl acetate. The organic layer was washed with brine,dried over MgSO₄, filtered and concentrated. The residue waschromatographed on silica gel eluting with a gradient starting withdichloromethane and ending with 50% acetone in dichloromethane to givethe title compound (0.019 g, 67% yield). ¹H NMR (300 MHz, DMSO-d₆), δppm 0.80-0.82 (m, 15 H), 1.41-1.58 (m, 2 H), 2.00 (s, 3 H), 2.54-2.57(m, 1 H), 2.71-2.79 (m, 3 H), 3.49 (s, 3 H), 3.55 (s, 3 H), 3.61-3.73(m, 2 H), 3.78-3.84 (m, 1 H), 4.03-4.24 (m, 3 H), 4.90 (d, J=5.5 Hz, 1H), 6.62 (d, J=9.6 Hz, 1 H), 7.09 (d, J=9.6 Hz, 1 H), 7.10-7.21 (m, 7H), 7.29-7.31 (m, 1 H), 7.57 (d, J=8.8 Hz, 1 H), 7.80 (d, J=9.9 Hz, 1H), 7.85-7.89 (m, 4 H), 8.64 (m, 1 H).

EXAMPLE 180methyl(1S,4R,6S,7S,10S)-7-benzyl-1,10-di-tert-butyl-6-hydroxy-15,15-dioxido-2,9-dioxido-4-(4-pyridin-2-ylbenzyl)-15-thia-3,8,11,14-tetraazahexadec-1-ylcarbamateEXAMPLE 180A tert-butylN-(2-{[(benzyloxy)carbonyl]amino}ethyl)-3-methyl-L-valinate

To a solution containing the product from Example 6F (0.20 g, 0.870mmol) in tetrahydrofuran (9.0 mL) were added triethylamine (0.120 mL,0.861 mmol) and N-(benzyloxycarbonyloxy)succinimide (0.217 g, 0.871mmol), and the mixture was stirred at room temperature for 12 hours. Thereaction was diluted with ethyl acetate, and washed three times with 10%Na₂CO₃. The organic was washed with brine and dried over MgSO₄ filteredand evaporated to give the crude product, which was used without furtherpurification.

EXAMPLE 180B N-(2-{[(benzyloxy)carbonyl]amino}ethyl)-3-methyl-L-valine

The product from Example 180A (0.870 mmol) was dissolved in an HClsolution in dioxane (5.0 mL, 4 N), and the mixture was stirred at roomtemperature for 12 hours. The solvent was evaporated to afford the titlecompound as the hydrochloride salt. The residue was used without furtherpurification.

EXAMPLE 180CN¹-[(1R,3S,4S)-4-({(2S)-2-[(2-(benzyloxy)carbonylaminoethyl)amino]-3,3-dimethylbanoyl}amino)-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]-N²-(methoxycarbonyl)-3-methyl-L-valinamide

A solution of the product of Example 1H (0.230 g, 0.432 mmol) intetrahydrofuran (4.0 mL) was treated with the product from Example 180B(0.435 mmol), DEPBT (0.20 g, 0.669 mmol), and N,N-diisopropylethylamine(0.75 mL, 4.31 mmol), stirred at 25° C. for 12 hours and partitionedbetween ethyl acetate and 10% Na₂CO₃ solution. The organic layer waswashed with additional 10% Na₂CO₃ solution and brine, dried over MgSO₄,filtered and concentrated. The residue was chromatographed on silica geleluting with a gradient starting with dichloromethane and ending withethyl acetate to give the title compound (0.203 g, 56% yield).

EXAMPLE 180DN¹-[(1R,3S,4S)-4-({(2S)-2-[(2-aminoethyl)amino]-3,3-dimethylbanoyl}amino)-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]-N²-(methoxycarbonyl)-3-methyl-L-valinamide

The product from Example 180C (0.200 g, 0.243 mmol) was dissolved inmethanol (2.5 mL) and 20% Pd(OH)₂ on carbon (0.040 g) was added, and thereaction was stirred under an atmosphere of hydrogen (balloon pressure)for 1.5 hours. The mixture was filtered through celite and the solventwas evaporated to give the title compound, which was used withoutfurther purification.

EXAMPLE 180Emethyl(1S,4R,6S,7S,10S)-7-benzyl-1,10-di-tert-butyl-6-hydroxy-15,15-dioxido-2,9-4-(4-pyridin-2-ylbenzyl)-15-thia-3,8,11,14-tetraazahexadec-1-ylcarbamate

To a solution of the product of Example 180D (0.015 g, 0.022 mmol) indichloromethane (0.20 mL) at room temperature were addeddiisopropylethylamine (0.011 mL, 0.063 mmol) and methanesulfonylchloride (0.0019 mL, 0.025 mmol) at room temperature. After 2 hourswater was added and the reaction was extracted with ethyl acetate. Theorganic layer was washed with brine, dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel elutingfirst with a gradient starting with dichloromethane and ending withethyl acetate and then with 5% methanol in ethyl acetate to give thetitle compound (0.011 g, 66% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm0.76 (s, 9 H), 0.77 (s, 9 H), 1.17-1.38 (m, 2 H), 1.52-1.60 (m, 1 H),2.04-2.16 (m, 1 H), 2.57-2.70 (m, 3 H), 2.75-2.88 (m, 7 H), 3.52-3.61(m, 4 ), 3.81 (d, J=9.6 Hz, 1 H), 3.95-4.03 (m, 1 H), 4.11-4.21 (m, 1H),4.93 (d, J=4.8 Hz, 1 H), 6.76 (t, J=5.9 Hz, 1 H), 6.87 (d, J=9.6 Hz, 1H), 7.10-7.25 (m, 7 H), 7.30-7.34 (m, 1 H), 7.56 (d, J=9.2 Hz, 1 H),7.83-7.96 (m, 5 H), 8.64 (m, 1 H).

EXAMPLE 181methyl(1S,4R,6S,7S,10S)-7-benzyl-1,10-di-tert-butyl-6-hydroxy-2,9,15-trioxo-4-(4-pyridin-2-ylbenzyl)-16-oxa-3,8,11,14-tetraazaheptadec-1-ylcarbamate

To a solution of the product of Example 180D (0.015 g, 0.022 mmol) indichloromethane (0.20 mL) at room temperature were addeddiisopropylethylamine (0.011 mL, 0.063 mmol) and methyl chloroformate(0.002 mL, 0.026 mmol) at room temperature. After 2 hours water wasadded and the reaction was extracted with ethyl acetate. The organiclayer was washed with brine, dried over MgSO₄, filtered andconcentrated. The residue was chromatographed on silica gel elutingfirst with a gradient starting with dichloromethane and ending withethyl acetate and then with 5% methanol in ethyl acetate to give thetitle compound (0.012 g, 74% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm0.75 (s, 18 H), 1.13-1.38 (m, 3 H), 1.52-1.62 (m, 1 H), 1.63-1.75 (m, 1H), 1.96-2.14 (m, 1 H), 2.53-2.92 (m, 8 H), 3.51 (s, 3 H), 3.51-3.58 (m,1 H), 3.56 (s, 3 H), 3.82 (d, J=9.9 Hz, 1 H), 3.94-4.02 (m, 1 H),4.11-4.19 (m, 1H), 4.92 (d, J=4.8 Hz, 1 H), 6.63-6.89 (m, 2H), 7.08-7.24(m, 8 H), 7.30-7.34 (m, 1 H), 7.54 (d, J=9.2 Hz, 1 H), 7.83-7.96 (m, 5H), 8.64 (m, 1 H).

EXAMPLE 182methyl(1S)-1-({[(1R,3S,4S)-4-{[(2S)-2-(1,1-dioxido-1,2,5-thiadiazolidin-2-yl)-3,3-dimethylbutanoyl]amino}-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl-2,2-dimethylpropylcarbamate

To a solution of the product of Example 180D (0.112 g, 0.163 mmol) indichloromethane (1.60 mL) at 0° C. were added diisopropylethylamine(0.14 mL, 0.80 mmol) and a solution of sulfuryl chloride indichloromethane (0.20 mL, 1 N), and the solution was allowed to warm toroom temperature. After 1 hour water was added and the reaction wasextracted with ethyl acetate. The organic layer was washed with brine,dried over MgSO₄, filtered and concentrated. The residue waschromatographed on silica gel eluting with a gradient starting withdichloromethane and ending with ethyl acetate to give the title compound(0.0093 g, 7.6% yield).

¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.74 (s, 9 H), 0.93 (s, 9 H), 1.13-1.33(m, 3 H), 1.52-1.64 (m, 1 H), 2.58-2.69 (m, 2 H), 2.73-2.81 (m, 2 H),2.87-2.97 (m, 1 H), 3.14-3.24 (m, 1 H), 3.37-3.42 (m, 1 H), 3.57 (s, 3H), 3.67 (s, 1 H), 3.79 (d, J=9.6 Hz, 1 H), 3.843.92 (m, 1 H), 4.09-4.20(m, 1H), 4.66 (d, J=6.6 Hz, 1 H), 6.85 (d, J=9.6 Hz, 1 H), 7.00 (t,J=6.6 Hz, 1 H), 7.11-7.26 (m, 7 H), 7.30-7.34 (m, 1 H), 7.52 (d, J=9.6Hz, 1 H), 7.74 (d, J=8.5 Hz, 1 H), 7.83-7.96 (m, 4 H), 8.64 (m, 1 H).

EXAMPLE 183methyl(5S,8S,10S,11S,14S)-1-benzyl-5-tert-butyl-10-hydroxy-14-[(methoxycarbonyl)amino]-15-methyl-3,6,13-trioxo-8-(4-pyridin-2-ylbenzyl)-2-oxa-4,7,12-triazahexadecan-16-oateEXAMPLE 183A 1-tert-butyl 4-methylN-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-aspartate

1-tert-butyl 4-methyl N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-aspartate(516 mg, 1.25 mmol) was dissolved in tetrahydrofuran (5 mL). Thesolution was cooled to 0° C. and (trimethylsilyl)-diazomethane (0.75 mL,2M) was added. Methanol (550 μL, 13 mmol) was added dropwise and thesolution was allowed to warm to ambient temperature over 1 hour. Thesolution was concentrated and placed under vacuum to afford the titlecompound as a colorless oil.

EXAMPLE 183B 1-tert-butyl 4-methylN-(9-phenyl-9H-fluoren-9-yl)-L-aspartate

Example 183A (1.25 mmol) was dissolved in acetonitrile (8 mL) anddiethylamine (0.39 mL, 3.8 mmol) was added and the solution was stirredat ambient temperature for 3 hours. The solution was concentrated andpurified by column chromatography on silica gel (20-100% ethylacetate/hexane) to give a colorless oil (176 mg, 69%). To all of thismaterial (176 mg, 0.9 mmol) was added dichloromethane (2 mL) and thesolution was treated with triethylamine (253 uL, 1.8 mmol) and stirredat ambient temperature for 15 minutes. Lead nitrate (192 mg, 0.6 mmol)was added, followed by a solution of 9-bromo-9-phenylfluorene (362 mg,1.1 mmol) in dichloromethane (3 mL) and stirring was continued atambient temperature for 4 hours. Methanol (8 mL) was added and stirringwas continued for 30 minutes. The solution was filtered and the filtratewas concentrated to give a crude residue which was taken up in 1:1 5%citric acid/ether (10 mL). The aqueous layer was extracted with ether (3times 5 mL), the organic extracts combined, washed with saturated brinesolution (10 mL) and dried (Na₂SO₄). The solution was filtered and thefiltrate concentrated to give a crude residue which was purified bycolumn chromatography on silica gel (10% ethyl acetate/hexane) to yielda colorless oil (308 mg, 80%):

EXAMPLE 183C 1-tert-butyl 4-methyl3-methyl-N-(9-phenyl-9H-fluoren-9-yl)-L-aspartate

Potassium bis(trimethylsilyl)amide in toluene (1.6 mL, 0.5M) was addedto tetrahydrofuran (3 mL) and cooled to −78° C. A solution of Example183B (300 mg, 0.66 mmol) in tetrahydrofuran (2 mL) was added dropwiseand stirring was continued at −78° C. for 20 minutes. Methyl iodide (102uL, 1.64 mmol) was added and the solution was stirred at −78° C. for 3hours. Potassium bis(trimethylsilyl)amide in toluene (1.6 mL, 0.5M) wasadded and the solution stirred for another 20 minutes at −78° C. Methyliodide (102 uL, 1.64 mmol) was added and the solution was warmed toambient temperature and stirred for 72 hours. To this solution was added10 mL of saturated NH₄Cl and 10 mL of H₂O. The resulting solution wasextracted with ethyl acetate (3 times 20 mL), the organic extracts werecombined, washed with saturated brine solution (20 mL) and dried(Na₂SO₄). The solution was filtered and the filtrate concentrated toyield a crude residue which was purified by column chromatography onsilica gel (3% ethyl acetate/hexane) to give the title compound (79 mg,25%).

EXAMPLE 183Dmethyl(5S,8S,10S,11S,14S)-11-benzyl-5-tert-butyl-10-hydroxy-14-[(methoxycarbonyl)amino]-15-methyl-3,6,13-trioxo-8-(4-pyridin-2-ylbenzyl)-2-oxa-4,7,12-triazahexadecan-16-oate

Example 183C (50 mg, 0.11 mmol) was dissolved in dichloromethane (1 mL)and cooled to 0° C. Trifluoroacetic acid (1 mL) was added and thesolution was stirred at 0° C. for 1 hour. The ice bath was removed andthe solution was allowed to warm to ambient temperature over 3 hours.The solution was concentrated, toluene (5 mL) was added and the solutionconcentrated again. The residue was placed under vacuum for 2 hours,dissolved in dioxane (1 mL). To this solution was added sodium hydroxide(120 μL, 3N) and methyl chloroformate (17 μL, 0.22 mmol) and thesolution was stirred and heated at 60° C. for 18 hours. The solution wascooled to ambient temperature and 4N HCl was added until the pH wasacidic, then H₂O (5 mL) was added and the solution was extracted withethyl acetate (3 times 5 mL) and the extracts combined and dried(Na₂SO₄), filtered and the filtrate concentrated to yield a cruderesidue which was purified by column chromatography on silica gel (10%methanol/chloroform) to give a tan solid (25 mg, 100%). To this solid(25 mg, 0.11 mmol) was added N,N-dimethylformamide (1 mL) followed byN-hydroxybenzotriazole (23 mg, 0.17 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (33 mg, 0.17 mmol),triethylamine (16 uL, 0.11 mmol) and the product from Example 2C (61 mg,0.11 mmol). The solution was stirred at ambient temperature for 18 hoursthen H₂O (5 mL) was added and the solution extracted with ether (3 times5 mL). The organic extracts were combined and washed with saturatedbrine (5 mL), dried (Na₂SO₄), filtered and the filtrate concentrated toyield a crude product which was purified by column chromatography onsilica gel (2% CH₃OH/CHCl₃) to yield a white solid (11 mg, 13%): ¹H NMRδ 8.73-8.61 (d, 1H), 7.89, 7.86 (d, 2H), 7.82-7.63 (m, 2H), 7.26-7.00(m, 8H), 6.73, 6.70 (d, 1H), 6.18-5.99 (m, 1H), 5.88, 5.85 (d, 1H),5.39-5.13 (br s, 1H), 4.43-4.29 (m, 1H), 4.21-4.01 (m, 1H), 3.94-3.81(m, 1H), 3.81-3.71 (m, 1H), 3.69 (s, 3H), 3.66 (s, 3H), 3.62 (s, 3H),3.37-3.19 (m, 1H), 3.00-2.63 (m, 3H), 1.26-1.17 (m, 3H), 0.92 (s, 9H).

EXAMPLE 184methyl(5S,8S,10S,11S,14S)-11-benzyl-5-tert-butyl-10-hydroxy-14-[(methoxycarbonyl)amino]-15,15-dimethyl-3,6,13-trioxo-8-(4-pyridin-2-ylbenzyl)-2-oxa-4,7,12-triazahexadecan-16-oateEXAMPLE 184A 1-tert-butyl 4-methyl3,3-dimethyl-N-(9-phenyl-9H-fluoren-9-yl)-L-aspartate

Potassium bis(trimethylsilyl)amide in toluene (1.6 mL, 0.5M) was addedto tetrahydrofuran (3 mL) and cooled to −78° C. A solution of Example183B (300 mg, 0.66 mmol) in tetrahydrofuran (2 mL) was added dropwiseand stirring was continued at −78° C. for 20 minutes. Methyl iodide (102uL, 1.64 mmol) was added and the solution was stirred at −78° C. for 3hours. Potassium bis(trimethylsilyl)amide in toluene (1.6 mL, 0.5M) wasadded and the solution stirred for another 20 minutes at −78° C. Methyliodide (102 uL, 1.64 mmol) was added and the solution was warmed toambient temperature and stirred for 72 hours. To this solution was added10 mL of saturated NH₄Cl and 10 mL of H₂O. The resulting solution wasextracted with ethyl acetate (3 times 20 mL), the organic extracts werecombined, washed with saturated brine solution (20 mL) and dried(Na₂SO₄). The solution was filtered and the filtrate concentrated toyield a crude residue which was purified by column chromatography onsilica gel (3% ethyl acetate/hexane) to give the title compound (125 mg,39% yield):

EXAMPLE 184Bmethyl(5S,8S,10S,11S,14S)-11-benzyl-5-tert-butyl-10-hydroxy-14-[(methoxycarbonyl)amino]-15,15-dimethyl-3,6,13-trioxo-8-(4-pyridin-2-ylbenzyl)-2-oxa-4,7,12-triazahexadecan-16-oate

Example 184A (50 mg, 0.11 mmol) was dissolved in dichloromethane (1 mL)and cooled to 0° C. Trifluoroacetic acid (1 mL) was added and thesolution was stirred at 0° C. for 1 hour. The ice bath was removed andthe solution was allowed to warm to ambient temperature over 3 hours.The solution was concentrated, toluene (5 mL) was added and the solutionconcentrated again. The residue was placed under vacuum for 2 hours,dissolved in dioxane (1 mL) and 10% sodium bicarbonate (0.25 mL). Withstirring, di-tert-butyl dicarbonate (47 mg, 0.22 mmol) was added and thesolution was stirred for 18 hours, the solution was concentrated and theresidue distributed between ether (5 mL) and H₂O (5 mL). Hydrochloricacid (0.25 mL, 0.5 M) was added and the aqueous layer was extracted withether (3 times 5 mL), the organic extracts combined and washed with H₂O(10 mL), dried (Na₂SO₄), filtered and the filtrate concentrated. Theresidue was purified by column chromatography on silica gel (10%CH₃OH/CHCl₃) to yield a tan solid (21 mg, 72%) which was dissolved inN,N-dimethylformamide (0.5 mL) and N-hydroxybenzotriazole (16 mg, 0.11mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (22 mg, 0.11 mmol),triethylamine (11 uL, 0.08 mmol) and the product from Example 2C (41 mg,0.08 mmol) were added. The solution was stirred at ambient temperaturefor 18 hours, H₂O (5 mL) was added, and the solution extracted withether (3 times 5 mL), the organic extracts combined, dried (Na₂SO₄),filtered and concentrated. The residue was purified by columnchromatography on silica gel (2% CH₃OH/CHCl₃) to yield a white solid (21mg, 35%) which was dissolved in tetrahydrofuiran (1 mL) and hydrochloricacid (1 mL, 4M). The solution was stirred at 60° C. for 3 hours, cooledto ambient temperature and concentrated. Dioxane (1 mL) was addedfollowed by sodium hydroxide (29 uL, 3N) and methyl chloroformate (4 uL,0.05 mmol) and the solution was stirred at 60° C. for 18 hours. Thesolution was cooled to ambient temperature and poured into 1:1 ethylacetate/HCl (1 N) (5 mL) and extracted with ethyl acetate (3 times 5mL), the organic extracts combined, dried (Na₂SO₄), filtered and thefiltrate concentrated to yield a crude product which was purified bycolumn chromatography on silica gel (2% CH₃OH/CHCl₃) to yield a whitesolid (10 mg, 50%): ¹H NMR δ 8.74-8.62 (d, 1H), 7.94-7.81 (d, 2H),7.80-7.63 (m, 2H), 7.29-7.08 (m, 8H), 6.44-6.30 (d, 1H), 6.13-5.97 (d,1H), 5.94-5.83 (d, 1H), 5.35-5.12 (br s, 1H), 4.28, 4.25 (d, 1H),4.23-4.09 (m, 1H), 4.03-3.90 (m, 1H), 3.80-3.68 (m, 1H), 3.71 (s, 3H),3.69 (s, 3H), 3.63 (s, 3H), 2.90-2.72 (m, 3H), 1.22 (s, 3H), 1.13 (s,3H), 0.92 (s, 3H).

EXAMPLE 185methyl(1S)-1-[({(1S,2S,4S)-1-benzyl-2-hydroxy-5-phenyl-4-[(thien-2-ylcarbonyl)amino]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

A Smith Process Vial (2-5 mL) was charged with a stir bar andPS-Carbodiimide resin (108 mg, 0.12 mmol.). To the vessel were addedthiophene-2-carboxylic acid (5.6 mg, 0.044 mmol.) d in 0.2 mL dimethylacetamide, 1-hydroxybenzotriazole hydrate (5.4 mg, 0.04 mmol.) in 0.5 mLacetonitrile (acetonitrile), diisopropylethylamine (16.7 mg, 0.12 mmol.)in 0.5 mL acetonitrile and the product of Example 23S (19.6 mg, 0.04mmol.) in 0.7 mL acetonitrile. The reaction vessel was sealed and heatedto 100° C. for 300 seconds in an Ermys Optimizer. After cooling thereaction mixture was transferred to a pre-packed 1 g column ofSi-Carbonate (>4 eq. of functionalized reagent), which had beenpreviously conditioned with methanol. The reaction products werecollected, and the solvents were evaporated. The crude residue wasdissolved in 1:1 dimethyl sulfoxide/methanol and purified by reversephase HPLC to give 8.7 mg (35%) of the title compound. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 0.83 (s, 9 H), 1.55-1.76 (m, 2 H), 2.64-2.83 (m, 4 H),3.55 (s, 3 H), 3.60 (t, J=6.26 Hz, 1 H), 3.88 (s, 1 H), 4.18 (d, J=7.63Hz, 1 H), 4.29 (s, 1 H), 7.01-7.25 (m, 12 H), 7.54 (d, J=8.85 Hz, 1 H),7.60 (d, J=3.66 Hz, 1 H), 7.66-7.68 (m, 1 H), 8.18 (d, J=8.85 Hz, 1 H).

EXAMPLE 186methyl(1S)-1-[({(1S,2S,4S)-1-benzyl-2-hydroxy-5-phenyl-4-[(thien-3-ylcarbonyl)amino]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate

Using the same procedure as in Example 185, substitutingthiophene-3-carboxylic acid in place of thiophene-2-carboxylic acid,gave 29% of the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.83 (s,9 H), 1.52-1.71 (m, 2 H), 2.64-2.83 (m, 4 H), 3.55 (s, 3 H), 3.60 (t,J=6.26 Hz, 1 H), 3.88 (s, 1 H), 4.19 (d, J=7.93 Hz, 1 H), 4.28 (s, 1 H),7.06-7.24 (m, 12 H), 7.37 (dd, J=4.88, 1.22 Hz, 1 H), 7.51 (dd, J=5.03,2.90 Hz, 1 H), 7.52-7.56 (m, 1 H), 7.94 (dd, J=3.05, 1.22 Hz, 1 H).

EXAMPLE 187methyl(1S)-1-{[((1S,2S,4S)-1-benzyl-2-hydroxy-4-{[(3-methylthien-2-yl)carbonyl]amino}-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamate

Using the same procedure as in Example 185, substituting3-methylthiophene-2-carboxylic acid in place of thiophene-2-carboxylicacid, gave 32% of the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm0.84 (s, 9 H), 1.52-1.75 (m, 2 H), 2.18 (s, 3 H), 2.65-2.85 (m, 4 H),3.56 (s, 3 H), 3.63 (t, J=6.10 Hz, 1 H), 3.88 (s, 1 H), 4.19 (s, 1 H),4.30 (s, 1 H), 6.88 (d, J=4.88 Hz, 1 H), 7.08-7.27 (m, 11 H), 7.46 (d,J=4.88 Hz, 1 H), 7.56 (d, J=9.15 Hz, 1 H), 7.64 (d, J=8.54 Hz, 1 H).

EXAMPLE 188methyl(1S)-1-{[((1S,2S,4S)-1-benzyl-2-hydroxy-4-{[(5-methylthien-2-yl)carbonyl]amino}-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamate

Using the same procedure as in Example 185, substituting5-methylthiophene-2-carboxylic acid in place of thiophene-2-carboxylicacid, gave 32% of the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm0.83 (s, 9 H), 1.52-1.73 (m, 2 H), 2.43 (s, 3 H), 2.62-2.85 (m, 4 H),3.55 (s, 3 H), 3.60 (t, J=6.26 Hz, 1 H), 3.87 (s, 1 H), 4.18 (s, 1 H),4.24 (s, 1 H), 6.78 (d, J=2.44 Hz, 1 H), 7.06-7.25 (m, 12 H), 7.40 (d,J=3.66 Hz, 1 H), 7.53 (d, J=8.85 Hz, 1 H).

EXAMPLE 189methyl(1S)-1-{[((1S,2S,4S)-1-benzyl-2-hydroxy-4-{[(1-methyl-1H-pyrrol-2-yl)carbonyl]amino}-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamate

Using the same procedure as in Example 185, substitutingN-1-methylpyrrole-2-carboxylic acid in place of thiophene-2-carboxylicacid, gave 30% of the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm0.84 (s, 9 H), 1.52-1.72 (m, 2 H), 2.65-2.87 (m, 4 H), 3.55 (s, 3 H),3.57-3.63 (m, 1 H), 3.70 (s, 3 H), 3.88 (s, 1 H), 4.14-4.32 (m, 2 H),5.96 (dd, J=3.81, 2.59 Hz, 1 H), 6.57 (dd, J=3.97, 1.83 Hz, 1 H), 6.81(t, J=1.98 Hz, 1 H), 7.03-7.26 (m, 12 H), 7.53 (d, J=9.15 Hz, 1 H).

EXAMPLE 190methyl(1S)-1-{[((1S,2S,4S)-1-benzyl-4-{[(3,5-dimethylisoxazol-4-yl)carbonyl]amino}-2-hydroxy-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamate

Using the same procedure as in Example 185, substituting3,5-dimethylisoxazole-4-carboxylic acid in place ofthiophene-2-carboxylic acid, gave 37% of the title compound. ¹H NMR (500MHz, DMSO-d₆) δ ppm 0.85 (s, 9 H), 1.54-1.75 (m, 2 H), 1.99 (s, 3 H),2.17 (s, 3 H), 2.57-2.64 (m, 1 H), 2.68-2.90 (m, 3 H), 3.56 (s, 3 H),3.59-3.67 (m, 1 H), 3.90 (s, 1 H), 4.19 (d, J=7.02 Hz, 1 H), 4.34 (s, 1H), 7.12 (t, J=7.02 Hz, 1 H), 7.14-7.30 (m, 10 H), 7.57 (d, J=9.15 Hz, 1H), 7.80 (d, J=8.85 Hz, 1 H).

EXAMPLE 191methyl(1S)-1-({[(1S,3S,4S)-4-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-5-phenyl-3-(phosphonooxy)-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamateEXAMPLE 191Adibenzyl(1S,3S)-1-((1S)-1-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-2-phenylethyl)-3-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-4-(4-pyridin-2-ylphenyl)butylphosphate

A solution of the compound of Example 111 (0.100 g, 0.124 mmol),dibenzyl diethylphosphoramidite (0.088 mL, 294 mmol), and 1H-tetrazole(0.045 g, 0.642 mmol) in tetrahydrofuran (1.2 mL) was stirred at roomtemperature for 12 hours. Dichloromethane (1.2 mL) was added and themixture was cooled to −45° C., followed by addition ofm-chloroperbenzoic acid (0.075 g, 0.434 mmol). After stirring for 30minutes at −45° C., the reaction was diluted with ethyl acetate andwashed twice with 10% Na₂CO₃ and then with brine. The organic phase wasdried over MgSO₄, filtered and evaporated. The residue was purified bychromatography on silica gel, eluting with a gradient starting withdichloromethane and ending with ethyl acetate, to give the titlecompound (0.104 g, 80% yield).

EXAMPLE 191Bmethyl(1S)-1-({[(1S,3S,4S)-4-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-5-phenyl-3-(phosphonooxy)-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate

To a solution of the product from Example 191A (0.100 g, 0.094 mmol) ina mixture of ethyl acetate (1.0 mL) and methanol (1.0 mL) were added asolution of HCl in dioxiane (0.006 mL, 4 N) and Pd(OH)₂ on carbon (0.027g, 20% by wt. Pd), and the mixture was stirred under an atmosphere ofhydrogen (balloon pressure) for 30 minutes. The reaction was filteredthrough celite and the solvent was evaporated. Methanol and water wereadded and the pH was adjusted to 9 by addition of NaHCO₃ (0.030 g), andpurified by chromatography using a C18 column, eluting with a gradientstarting with water and ending with methanol, to give the title compoundas a disodium salt (0.066 g, 76% yield). ¹H NMR (300 MHz, MeOH-d₄), δppm 0.79 (s, 9 H), 1.01 (s, 9 H), 2.76-3.01 (m, 6 H), 3.13-3.19 (m, 1H), 3.60 (s, 3 H), 3.99 (s, 1 H), 4.09 (s, 1 H), 4.29-4.47 (m, 2 H),4.34 (s, 3 H), 6.94-7.01 (m, 3 H), 7.13-7.15 (m, 2 H), 7.27-7.39 (m, 8H), 7.78-7.89, (m, 4 H), 8.55-8.57 (m, 1 H).

EXAMPLE 192methyl(1S)-1-({[(1R,3S,4S)-4-{[(2S)-2-(3-{[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-methyl}-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-5-phenyl-3-(phosphonooxy)-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamateEXAMPLE 192Adibenzyl(1S,3R)-1-((1S)-1-{[(2S)-2-(3-{[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]methyl}-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-2-phenylethyl)-3-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-4-(4-pyridin-2-ylphenyl)butylphosphate

A solution of the compound of Example 50 (0.100 g, 0.116 mmol), dibenzyldiethylphosphoramidite (0.080 mL, 267 mmol), and 1H-tetrazole (0.040 g,0.571 mmol) in tetrahydrofuran (1.0 mL) was stirred at room temperaturefor 12 hours. Dichloromethane (1.0 mL) was added and the mixture wascooled to −45° C., followed by addition of m-chloroperbenzoic acid(0.072 g, 0.417 mmol). After stirring for 30 minutes at −45° C., thereaction was diluted with ethyl acetate and washed twice with 10% Na₂CO₃and then with brine. The organic phase was dried over MgSO₄, filteredand evaporated. The residue was purified by chromatography on silicagel, eluting with a gradient starting with dichloromethane and endingwith ethyl acetate, to give the title compound (0.104 g, 80% yield).

EXAMPLE 192Bmethyl(1S)-1-({[(1R,3S,4S)-4-{[(2S)-2-(3-{[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]methyl}-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-5-phenyl-3-(phosphonooxy)-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate

To a solution of the product from Example 192A (0.104 g, 0.093 mmol) ina mixture of ethyl acetate (0.5 mL) and methanol (0.5 mL) were added asolution of HCl in dioxane (0.046 mL, 4 N) and Pd(OH)₂ on carbon (0.020g, 20% by wt. Pd), and the mixture was stirred under an atmosphere ofhydrogen (balloon pressure) for 30 minutes. The reaction was filteredthrough celite and the solvent was evaporated. Methanol and water wereadded and the pH was adjusted to 9 by addition of NaHCO₃ (0.045 g), andpurified by chromatography using a C18 column, eluting with a gradientstarting with water and ending with methanol, to give the title compoundas the disodium salt (0.059 g, 65% yield). ¹H NMR (300 MHz, MeOH-d₄), δppm 0.88 (s, 9 H), 0.89 (s, 9 H), 1.52 (s, 3 H), 1.53 (s, 3 H),1.65-1.74 (m, 1 H), 2.03-2.06 (m, 1 H), 2.31 (q, J=9.3 Hz, 1 H),2.91-3.04 (m, 5 H), 3.18 (q, J=9.8 Hz, 1 H), 3.26-3.28 (m, 1 H), 3.64(s, 3 H), 3.97 (s, 1 H), 4.06-4.08 (m, 1 H), 4.14 (s, 1 H), 4.39 (d,J=15.6 Hz, 1 H), 4.43-4.49 (m, 2 H), 4.57 (d, J=15.6 Hz, 1 H), 6.97-7.05(m, 3 H), 7.16-7.21 (m, 3 H), 7.30-7.32 (m, 1 H), 7.37 (d, J=7.8 Hz, 2H), 7.52 (d, J=7.3 Hz, 1 H), 7.75-7.88 (m, 5 H), 8.57 (m, 1 H).

EXAMPLE 193(1S,3S)-1-((1S)-1-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-2-phenylethyl)-3-({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-4-(4-pyridin-2-ylphenyl)butyl(2S)-2-aminopropanoate EXAMPLE 193A(1S,3S)-1-((1S)-1-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-2-phenylethyl)-3-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-4-(4-pyridin-2-ylphenyl)butylN-(tert-butoxycarbonyl)-L-alaninate

To a solution containing the compound of Example 111 (0.100 g, 0.124mmol), N-(tert-butoxycarbonyl) L-alanine (0.028 g, 0.147 mmol)), and4(dimethylamino)pyridine (0.018 g, 0.147 mmol) in N,N-dimethylformamide(1.0 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDAC) (0.029 g, 0.151 mmol) and the mixture was stirredat room temperature for 2 hours. Two subsequent additions ofN-(tert-butoxycarbonyl) L-alanine (0.028 g) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC)(0.029 g) were made at two hour intervals. The solvent was evaporatedand the reaction mixture was partitioned between ethyl acetate andaqueous NaHCO₃. The organic layer was washed with brine, dried overMgSO₄, filtered and evaporated. The residue was purified bychromatography on silica gel, eluting with a gradient starting withchloroform and ending with 66% ethyl acetate in chloroform, to give thetitle compound (0.100 g, 82%).

EXAMPLE 193B (1S,3S)-1-((1S)-1-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-2-phenylethyl)-3-({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-4-(4-pyridin-2-ylphenyl)butyl(2S)-2-aminopropanoate

To a solution of the product of Example 193A (0.098 g, 0.037 mmol) indichloromethane (1.0 mL) at room temperature was added a solution of HClin dioxane (0.13 mL, 4 N), and the mixture was stirred at roomtemperature for 3 hours. The solvent was evaporated to give the titlecompound as the bis hydrochloride salt (0.089 g). ¹H NMR (300 MHz,DMSO-d₆), δ ppm 0.88 (s, 9 H), 0.91 (s, 9 H), 1.57 (d, J=7.4 Hz, 1 H),1.69-1.74 (m, 2 H), 2.27 (q, J=9.6 Hz, 1 H), 2.53-2.56 (m, 2 H),2.72-2.85 (m, 3 H), 2.94 (q, J=8.8 Hz, 1 H), 3.17-3.24 (m, 1 H), 3.46(s, 3 ), 3.87 (d, J=9.9 Hz, 1 H), 4.14 (s, 1 H), 4.19-4.37 (m, 4 H),4.31 (s, 2 H), 4.60-4.70 (m, 1 H), 5.14 (t, J=7.4 Hz, 1 H), 6.66 (d,J=9.6 Hz, 1 H), 7.00-7.08 (m, 3 H), 7.08-7.16 (m, 2 H), 7.26-7.47 (m, 8H), 7.90-7.99 (m, 6 H), 8.46-8.57 (m, 3 H), 8.67-8.68 (m, 1 H).

EXAMPLE 194methyl(1S)-1-({[(1R,3S,4S)-4)-{(2S)-3,3-dimethyl-2-[3-({6-[1-methyl-1-(phosphonooxy)ethyl]pyridin-2-yl}methyl)-2-oxoimidazolidin-1-yl]butanoyl}amino)-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamateEXAMPLE 194Atert-butyl(1S,3R)-1-((1S)-1-{[(2S)-2-(3-{[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]methyl}-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-2-phenylethyl)-3-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-4-(4-pyridin-2-ylphenyl)butylcarbonate

To a solution of the product from Example 50 (1.0 g, 1.16 mmol) intetrahydrofuran (11.0 mL) were added 4-(dimethylamino)pyridine, (0.155g, 1.27 mmol) and di-tert-butyl dicarbonate (0.33 g, 1.51 mmol), and themixture was stirred at room temperature for 12 hours. Ethyl acetate wasadded and the organic layer was washed with dilute NaHCO₃, and brine,dried over MgSO₄ filtered and concentrated to give the crude product,which was used without further purification.

EXAMPLE 194B(1S,3R)-1-((1S)-1-{[(2S)-2-(3-{[6-(1-{[bis(benzyloxy)phosphoryl]oxy}-1methylethyl)pyridin-2-yl]methyl}-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-2-phenylethyl)-3-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-4-(4-pyridin-2-ylphenyl)butyltert-butyl carbonate

A solution of the compound of Example 194A (1.16 mmol), dibenzyldiethylphosphoramidite (1.25 mL, 4.17 mmol), and 1H-tetrazole (0.40 g,5.71 mmol) in tetrahydrofuran (11.0 mL) was stirred at room temperaturefor 12 hours. Dichloromethane (11.0 mL) was added and the mixture wascooled to −45° C., followed by addition of m-chloroperbenzoic acid (1.15g, 6.66 mmol). After stirring for 1 hour at −45° C., the reaction wasdiluted with ethyl acetate and washed twice with 10% Na₂CO₃ and thenwith brine. The organic phase was dried over MgSO₄, filtered andevaporated. The residue was purified by chromatography on silica gel,eluting with a gradient starting with dichloromethane and ending with75% ethyl acetate in dichloromethane, to give the title compound (0.684g, 48% yield over two steps).

EXAMPLE 194Cmethyl(1S)-1-({[(1R,3S,4S)-4-({(2S)-3,3-dimethyl-2-[3-({6-[1-methyl-1-(phosphonooxy)ethyl]pyridin-2-yl}methyl)-2-oxoimidazolidin-1-yl]butanoyl}amino)-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate

To a solution of the product from Example 194B (0.684 g, 0.559 mmol) indichloromethane (10.0 mL) was added trifluoroacetic acid (10.0 mL), andthe mixture was stirred at room temperature for 4 hours, and the solventwas evaporated. Methanol and water were added and the pH was adjusted to8 by addition of NaHCO₃, and the mixture was purified by chromatographyusing a C18 column, eluting with a gradient starting with water andending with methanol, to give the title compound as the disodium salt(0.342 g, 62% yield). ¹H NMR (300 MHz, MeOH-d₄), δ ppm 0.86 (s, 9 H),0.90 (s, 9 H), 1.43-1.53 (m, 1 H), 1.66-1.75 (m, 1 H), 1.78 (s, 3 H),1.81 (s, 3 H), 2.28-2.36 (m, 1 H), 2.68-3.06 (m, 5 H), 3.19 3.27 (m, 2H), 3.66 (s, 3 H), 3.77 (d, J=10.3 Hz, 1 H), 3.88 (s, 1 H), 4.00 (s, 1H), 4.04-4.08 (m, 1 H), 4.36 (d, J=15.4 Hz, 1 H), 4.41-4.51 (m, 1 H),4.58 (d, J=15.4 Hz, 1 H), 7.07-7.16 (m, 6 H), 7.32-7.36 (m, 3 H),7.69-7.91 (m, 5 H), 8.58 (m, 1 H).

EXAMPLE 195(3S,5S,8S)-3-((1S)-1-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]-amino}-2-phenylethyl)-8-tert-butyl-7,10-dioxo-5-(4-pyridin-2-ylbenzyl)-2,11-dioxa-6,9-diazadodec-1-yl-(dimethylamino)acetateEXAMPLE 195AN¹-[(1S,3S,4S)-4-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-3-[(methylthio)methoxy]-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]-N²-(methoxycarbonyl)-3-methyl-L-valinamide

To a solution of the compound of Example 111 (1.4 g, 1.74 mmol) andmethyl sulfide (3.2 mL, 43.3 mmol) in acetonitrile (18 mL) at 0° C. wasadded benzoyl peroxide (1.7 g), and the mixture was warmed to roomtemperature and stirred for 30 minutes. The reaction was cooled to 0° C.and benzoyl peroxide (1.7 g) was added, and the mixture was warmed toroom temperature and stirred for 30 minutes. Water was added and thereaction was diluted with ethyl acetate and washed with 10% Na₂CO₃ andbrine. The organic was dried over MgSO₄, filtered and evaporated. Theresidue was chromatographed on silica gel eluting with a gradientstarting with dichloromethane and ending with ethyl acetate to give thetitle compound (1.24 g, 83% yield).

EXAMPLE 195B(3S,5S,8S)-3-((1S)-1-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-2-phenylethyl)-8-tert-butyl-7,10-dioxo-5-(4-pyridin-2-ylbenzyl)-2,11-dioxa-6,9-diazadodec-1-yl(dimethylamino)acetate

To a solution of the product from Example 195A (0.045 g, 0.052 mmol) in1,2-dichloromethane (1.5 mL) were added molecular sieves (4 Å, 0.24 g),N,N-dimethylglycine hydrochloride (0.075 g, 0.537 mmol), followed byN-iodosuccinimide (0.013 g, 0.058 mmol), and the mixture was stirred atroom temperature for 2 hours. The reaction was filtered through celite.The filtrate was diluted with ethyl acetate and was washed with amixture of dilute NaHCO₃ and Na₂S₂O₃, dried over MgSO₄, filtered andevaporated. The residue was dissolved in ether and 2 equivalents of 4 NHCl in dioxane were added. The crude product was purified bychromatography on silica gel eluting with a gradient starting withdichloromethane and ending with methanol to give the title compound asthe bis hydrochloride salt (0.037 g, 77% yield). ¹H NMR (300 MHz,DMSO-d₆), δ ppm 0.87 (s, 9 H), 0.88 (s, 9 H), 1.60-1.73 (m, 2 H), 2.22(s, 6 H), 2.29 (q, J=9.6 Hz, 1 H), 2.54-2.84 (m, 6 H), 2.93 (q, J=8.8Hz, 1 H), 3.08-3.24 (m, 4 H), 3.53 (s, 3 H), 3.72-3.76 (m, 1 H), 3.87(d, J=9.6 Hz, 1 H), 4.11-4.35 (m, 5 H), 5.26 (d, J=6.6 Hz, 1 H), 5.37(d, J=6.6 Hz, 1 H), 6.78 (d, J=9.6 Hz, 1 H), 6.94-7.15 (m, 5 H),7.22-7.40 (m, 8 H), 7.82-7.95 (m, 6 H), 8.63 (m, 1 H).

EXAMPLE 196(1S,3S)-1-((1S)-1-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-2-phenylethyl)-3-({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-4-(4-pyridin-2-ylphenyl)butyl(phosphonooxy)methyl carbonate EXAMPLE 196A(1S,3S)-1-((1S)-1-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-2-phenylethyl)-3-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-4-(4-pyridin-2-ylphenyl)butylchloromethyl carbonate

To a solution of the product from Example 111 (0.050 g, 0.062 mmol) inpyridine (0.60 mL) at room temperature was added chloromethylchloroformate (0.007 mL, 0.079 mmol), and the mixture was stirred for 30minutes. Additional chloromethyl chloroformate (0.007 mL) was added andthe reaction was stirred for 30 minutes. The reaction was diluted withethyl acetate and washed with dilute NaHCO₃ and brine. The organic wasdried over MgSO₄, filtered and evaporated to give the title compound(0.047 g, 84% yield), which was used without further purification.

EXAMPLE 196B(1S,3S)-1-((1S)-1-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]-amino}-2-phenylethyl)-3-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-4-(4-pyridin-2-ylphenyl)butyl{[bis(benzyloxy)phosphoryl]oxy}methylcarbonate

To a solution of dibenzyl phosphate (0.175 g, 0.62 mmol) in methanol(6.0 mL) was added a solution of tetramethylammonium hydroxide inmethanol (0.23 mL, 25%), and the solvent was evaporated. To this saltwas added a solution of the product from Example 196A (0.047 g, 0.052mmol) in N,N-dimethylformamide (0.60 mL) and the reaction was stirred at50° C. for 5 hours. The reaction was diluted with ethyl acetate andwashed with dilute NaHCO₃ and brine. The organic was dried over MgSO₄,filtered and evaporated. The compound was purified by chromatography onsilica gel eluting with a gradient starting with chloroform and endingwith 66% ethyl acetate in chloroform to give the title compound (0.022g, 37% yield).

EXAMPLE 196C(1S,3S)-1-((1S)-1-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-2-phenylethyl)-3-({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-4-(4-pyridin-2-ylphenyl)butyl(phosphonooxy)methyl carbonate

To a solution of the product from Example 196B (0.125 g, 0.110 mmol) ina mixture of ethyl acetate (1.0 mL) and methanol (1.0 mL) was addedPd(OH)₂ on carbon (0.10 g, 20% by wt. Pd), and the mixture was stirredunder an atmosphere of hydrogen (balloon pressure) for 1 hour. Thereaction was filtered through celite and the solvent was evaporated. Thecompound was purified by chromatography on silica gel, eluting with agradient starting with 20% methanol in ethyl acetate and ending with 50%methanol in ethyl acetate, to give the title compound (0.078 g, 74%yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.86 (s, 9 H), 0.87 (s, 9 H),1.73-1.78 (m, 2 H), 2.17 (q, J=9.2 Hz, 1 H), 2.58-2.83 (m, 5 H), 2.91(q, J=8.8 Hz, 1 H), 3.09-3.17 (m, 2 H), 3.48 (s, 3 H), 3.86 (d, J=9.9Hz, 1 H), 4.18 (s, 1 H), 4.20-4.31 (m, 1 H), 4.31 (s, 2 H), 4.46-4.55(m, 1 H), 4.94 (t, J=7.0 Hz, 1 H), 5.49-5.59 (m, 2 H), 6.72 (d, J=9.9Hz, 1 H), 6.97-7.06 (m, 3 H), 7.11-7.17 (m, 2 H), 7.23-7.40 (m, 9 H),7.81-7.92 (m, 4 H), 8.01 (d, J=8.5 Hz, 1 H), 8.17 (d, J=9.6 Hz, 1 H),8.63 (m, 1 H).

EXAMPLE 197(5S,7S,10S)-5-((1S)-1-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-2-phenylethyl)-10-tert-butyl-3,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-2,4,13-trioxa-8,11-diazatetradec-1-yl(dimethylamino)acetate

To a solution of the product from Example 196A (0.202 g, 0.22 mmol) inN,N-dimethylformamide (1.0 mL) were added N,N-dimethylglycinehydrochloride (0.156 g, 1.12 mmol), and N,N-diisopropylethylamine (0.58mL, 3.33 mmol), and the reaction was stirred at room temperature for 68hours. The reaction was diluted with ethyl acetate and washed withdilute NaHCO₃ and brine. The organic was dried over MgSO₄, filtered andevaporated. The compound was purified by chromatography on silica geleluting with a gradient starting with 5% methanol in chloroform andending with 50% methanol in chloroform to give the title compound (0.085g, 40% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm 0.86 (s, 9 H), 0.89 (s,9 H), 1.75-1.85 (m, 2 H), 2.24 (q, J=9.2 Hz, 1 H), 2.57-2.84 (m, 5 H),2.93 (q, J=8.9 Hz, 1 H), 3.13-3.23 (m, 1 H), 3.18 (s, 3 H), 3.19 (s, 3H), 3.49 (s, 3 H), 3.86 (d, J=9.6 Hz, 1 H), 4.17 (s, 1 ), 4.17-4.26 (m,1 H), 4.31 (s, 2 H), 4.48-4.56 (m, 1 H), 4.94 (t, J=6.6 Hz, 1 H), 5.68(s, 2 H), 6.71 (d, J=9.6 Hz, 1 H), 7.01-7.06 (m, 3 H), 7.14-7.17 (m, 2H), 7.24-7.41 (m, 8 H), 7.82-7.93 (m, 4 H), 8.03 (d, J=8.5 Hz, 1 H),8.17 (d, J=9.2 Hz, 1 H), 8.63 (m, 1 H).

EXAMPLE 198(5S,8S,10S)-10-((1S)-1-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-2-phenylethyl)-5-tert-butyl-3,6,12-trioxo-8-(4-pyridin-2-ylbenzyl)-2,11-dioxa-4,7-diazapentadecan-15-oicacid

A solution of Example 111 (60 mg, 0.074 mmol) in tetrahydrofuran (0.25mL) and diethyl ether (0.5 mL) was treated with succinic anhydride (8.2mg, 0.082 mmol) and dicyclohexylamine (16.3 μL, 0.082 mmol) at 25° C.for 6 h. Over the next 2 days more succinic anhydride (16.4 mg, 0.16mmol) was added in portions. The mixture was partitioned betweendichloromethane and 10% citric acid. The organic layer was separated,washed with brine, dried over MgSO₄, and the solvents were evaporated togive the title compound (66 mg, 98%). ¹H NMR (300 MHz, DMSO-d₆) δ ppm0.86(s, 9H), 0.89(s, 9H), 1.25(m, 1H), 1.66(m, 1H), 2.34-2.24(m, 1H),2.83-2.55(m, 9H), 2.98-2.89(m, 1H), 3.22-2.12(m, 1H), 3.46(s, 3H),3.86-3.83(d, J=9.93 Hz, 1H), 4.48-1.09(m, 6H), 5.15-5.10(m, 1H),6.61-6.58(d, J=9.56 Hz, 1H), 7.05-7.00(m, 3H), 7.13-7.11(m, 2H),7.31-7.25(m, 4H), 7.44-7.36(m, 3H), 7.92-7.87(m, 3H), 7.96(m, 2H),8.06-8.02(d, J=9.56 Hz, 1H), 8.68-8.66(m, 1H).

EXAMPLE 199(1S,3S)-1-((1S)-1-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]-amino}-2-phenylethyl)-3-({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-4-(4-pyridin-2-ylphenyl)butyl{[ethoxy(hydroxy)phosphoryl]oxy}methylcarbonate

To a solution of ethyl phosphate (0.170 g, 1.35 mmol) in methanol (6.0mL) was added a solution of tetramethylammonium hydroxide in methanol(0.50 mL, 25%), and the solvent was evaporated. To this salt was added asolution of the product from Example 196A (0.150 g, 0.167 mmol) inN,N-dimethylformamide (2.0 mL) and the reaction was stirred at 50° C.for 20 hours and then at 70° C. for 8 hours. The reaction was dilutedwith ethyl acetate and washed with water and brine. The organic wasdried over MgSO₄, filtered and evaporated. Methanol and water were addedand the pH was adjusted to 8 by addition of NaHCO₃, and the mixture waspurified by chromatography using a C18 column, eluting with a gradientstarting with water and ending with methanol, to give the title compoundas a monosodium salt (0.035 g, 20% yield). ¹H NMR (300 MHz, DMSO-d₆), δppm 0.85 (s, 9 H), 0.87 (s, 9 H), 1.10 (t, J=7.0 Hz, 3 H), 1.67-1.84 (m,2 H), 2.24 (q, J=9.2 Hz, 1 H), 2.54-2.96 (m, 6 H), 3.11-3.19 (m, 1 H),3.48 (s, 3 H), 3.69 (m, 2 H), 3.86 (d, J=9.6 Hz, 1 H), 4.20 (s, 1 H),4.274.36 (s, 3 H), 4.44-4.51 (m, 1 H), 4.80-4.85 (m, 1 H), 5.37-5.51 (m,2 H), 6.89 (d, J=9.9 Hz, 1 H), 7.00-7.02 (m, 3 H), 7.12-7.15 (m, 2 H),7.23-7.40 (m, 8 H), 7.81-7.92 (m, 4 H), 8.13 (d, J=9.2 Hz, 1 H), 8.33(d, J=9.2 Hz, 1 H), 8.63 (m, 1 H).

EXAMPLE 200methyl(1S,4S,6S)-6-((1S)-1-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-2-phenylethyl)-1-tert-butyl-10-hydroxy-10-oxido-2-oxo-4-(4-pyridin-2-ylbenzyl)-7,9,11-trioxa-3-aza-10-phosphatridec-1-ylcarbamate

To a solution of the product from Example 195A (0.050 g, 0.058 mmol) in1,2-dichloromethane (1.0 mL) at 0° C. were added molecular sieves (4 Å,0.200 g), ethyl phosphate (0.100 g, 0.794 mmol), followed byN-iodosuccinimide (0.016 g, 0.071 mmol), and the mixture was stirred atroom temperature for 30 minutes. The reaction was filtered throughcelite. The filtrate was diluted with ethyl acetate and was washed witha mixture of dilute NaHCO₃ and Na₂S₂O₃, dried over MgSO₄, filtered andevaporated. Methanol and water were added and the pH was adjusted to 8by addition of NaHCO₃, and the mixture was purified by chromatographyusing a C18 column, eluting with a gradient starting with water andending with methanol, to give the title compound as the monosodium salt(0.040 g, 74% yield). ¹H NMR (300 MHz, DMSO-d₆), δ ppm ¹H NMR (300 MHz,DMSO-d₆), δ ppm 0.67 (s, 9 H), 0.92 (s, 9 H), 1.11 (t, J=7.0 Hz, 3 H),1.47-1.60 (m, 1 H), 1.81-1.92 (m, 1 H), 2.26 (q, J=9.2 Hz, 1 H),2.54-2.93 (m, 6 H), 3.07-3.13 (m, 1 H), 3.52 (s, 3 H), 3.67-3.76 (m, 1H), 3.92-4.11 (m, 5 H), 4.28 (s, 2 H), 4.94-5.04 (m, 2 H), 6.98-7.04(m,5 H), 7.23-7.38 (m, 8 H), 7.63 (d, J=9.2 Hz, 1 H), 7.81-7.92 (m, 4 H),8.63 (m, 1 H).

EXAMPLE 201methyl(1S,4S,6S)-6-((1S)-1-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-2-phenylethyl)-1-tert-butyl-10,10-dihydroxy-10-oxido-2-oxo-4-(4-pyridin-2-ylbenzyl)-7,9-dioxa-3-aza-10-phosphadec-1-ylcarbamate

To a solution of the product from Example 195A (1.24 g, 1.43 mmol) intetrahydrofuran (7.0 mL) at room temperature were added molecular sieves(4 Å, 3.5 g), a solution of phosphoric acid in N,N-dimethylformamide(14.0 mL, 0.5 M), and N-iodosuccinimide (0.650 g, 2.89 mmol), and themixture was stirred at room temperature for 45 minutes. The reaction wasdiluted with methanol (250 mL) and filtered through celite. The filtratewas treated with Na₂S₂O₃ (saturated) and the pH was adjusted to 9 with10% Na₂CO₃. The methanol was evaporated and the mixture was purified bychromatography using a C18 column, eluting with a gradient starting withwater and ending with methanol, to give the title compound as thedisodium salt (0.76 g, 55% yield). ¹H NMR (300 MHz, MeOH-d₄), δ ppm 0.86(s, 9 H), 0.95 (s, 9 H), 1.69-1.77 (m, 1H), 2.02-2.20 (m, 2 H),3.73-3.02 (m, 6 H), 3.17-3.23 (m, 1 H), 3.56 (s, 3 H), 3.81-3.86 (m, 1H), 3.96 (s, 1 H), 4.07 (s, 1 H), 4.35 (s, 2 H), 4.41-4.50 (m, 1 H),5.06 (dd, J=9.0, 5.3 Hz, 1 H), 5.20 (dd, J=8.8, 5.5 Hz, 1 H), 6.95-7.03(m, 3 H), 7.14-7.17 (m, 2 H), 7.27-7.39 (m, 8 H), 7.79-7.89, (m, 4 H),8.56 (m, 1 H).

EXAMPLE 202methyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-bis(tert-butyl)-2,9,12-trioxo-5-(phosphonooxy)-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamateEXAMPLE 202Amethyl(1S,4S,5S,7S,10S)-4benzyl-1,10-bis(tert-butyl)-2,9,12-trioxo-5-{[bis(benzyloxy)phosphoryl]oxy}-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate

A solution of Example 2D (98.7 mg, 0.14 mmol) in tetrahydrofuran (1.4mL) was treated with diethyl dibenyzlphosphoramidite (99 uL, 0.28 mmol)and tetrazole (49 mg, 0.7 mmol) at 25° C. for 16 h. The mixture wascooled to −45° C. and treated with m-chloroperbenzoic acid (70%, 87 mg,0.35 mmol) and stirred for 1 h. The mixture was quenched with 10% sodiumcarbonate, warmed to 25° C., and the organic layer was separated, driedover MgSO₄, and the solvents were evaporated. The crude residue waspurified by silica gel chromatography using dichloromethane to 100%ethyl acetate to give the title compound (110 mg, 81%).

EXAMPLE 202Bmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-bis(tert-butyl)-2,9,12-trioxo-5-(phosphonooxy)-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate

A solution of Example 202A (105 mg, 0.109 mmol) in ethyl acetate (2 mL)and methanol (2 mL) was treated with a hydrogen balloon, 20% Pd(OH)₂ (8mg, 0.011 mmol), and 4N HCl in dioxane (27 uL, 0.109 mmol) at 25° C. for1 h. The mixture was filtered through Celite, rinsed with methanol,combined with water (1 mL) and treated with sodium bicarbonate (71 mg,0.84 mmol). This mixture was purified using reverse phase chromatographyon C18 column using 0-100% methanol/water to give the title compound asthe disodium salt (80 mg, 89%). ¹H NMR (300 MHz, CD₃OD) δ ppm 0.69(s,9H), 0.99(s, 9H), 1.69(m, 1H), 2.10(m, 1H), 2.88-2.76(m, 3H),3.06-2.98(m, 1H), 3.62(s, 3H), 3.63(s, 3H), 3.90(s, 1H), 3.99(s, 1H),4.32-4.19(m, 3H), 7.13-7.01(m, 3H), 7.21-7.19(m, 2H), 7.32-7.29(m, 3H),7.88-7.76(m, 4H), 8.57(m, 1H).

849122 EXAMPLE 203 DAVID DEGOEYmethyl(1S,4S,5S,7S,10S)-7-benzyl-1,10-bis(tert-butyl)-2,9,12-trioxo-5-[(phosphonooxy)methoxy]-4-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamateEXAMPLE 203Amethyl(1S)-1-({[(1S,3S,4S)-1-benzyl-4-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-3-[(methylthio)methoxy]-5-(4-pyridin-2-ylphenyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate

To a solution of the compound of Example 25 (0.125 g, 0.178 mmol) andmethyl sulfide (0.405 mL, 5.48 mmol) in acetonitrile (0.75 mL) at 0° C.was added benzoyl peroxide (0.63 g, 2.60 mmol), and the mixture wasstirred at 0° C. for 1 hour. The reaction was diluted with ethyl acetateand washed with 10% Na₂CO₃ and brine. The organic was dried over MgSO₄,filtered and evaporated. The residue was chromatographed on silica geleluting with a gradient starting with dichloromethane and ending withethyl acetate to give the title compound (0.104 g, 77% yield).

EXAMPLE 203Bmethyl(1S,4S,5S,7S,10S)-7-benzyl-1,10-bis(tert-butyl)-2,9,12-trioxo-5-[(phosphonooxy)methoxy]-4-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate

To a solution of the product from Example 203A (0.104 g, 0.136 mmol) intetrahydrofuran (2.0 mL) at room temperature were added molecular sieves(4 Å, 0.40 g) and phosphoric acid (0.125 g, 1.28 mmol), and the reactionwas cooled to 0° C., followed by addition of N-iodosuccinimide (0.060 g,0.267 mmol), and the mixture was stirred at room temperature for 30minutes. The reaction was diluted with methanol and filtered throughcelite. The filtrate was treated with Na₂S₂O₃ (saturated) and the pH wasadjusted to 9 with 10% Na₂CO₃. The methanol was evaporated and themixture was purified by chromatography using a C18 column, eluting witha gradient starting with water and ending with methanol, to give thetitle compound as the disodium salt (0.060 g, 52% yield). ¹H NMR (300MHz, MeOH-d₆), δ ppm 0.83 (s, 9 H), 0.85 (s, 9 H), 1.65-1.74 (m, 1H),1.97-2.06 (m, 1 H), 2.62-2.79 (m, 2 H), 2.87-3.05 (m, 2 H), 3.49 (s, 3H), 3.67 (s, 3 H), 3.71-3.75 (m, 1 H), 3.92 (s, 1 H), 3.95 (s, 1 H),4.17-4.27 (m, 1 H), 4.37-4.42 (m, 1 H), 5.05 (dd, J=8.5, 5.5 Hz, 1 H),5.15 (dd, J=92, 5.5 Hz, 1 H), 7.07-7.16 (m, 5 H), 7.28-7.33 (m, 1 H),7.37 (d, J=8.1 Hz, 2 H), 7.76-7.88 (m, 4 H), 8.56 (m, 1 H).

EXAMPLE 204methyl(1S,4S,5S,7S,10S)-4benzyl-1,10-bis(tert-butyl)-2,9,12-trioxo-5-[(phosphonooxy)methoxy]-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamateEXAMPLE 204Amethyl(1S)-1-({[(1S,2S,4S)-1-benzyl-4-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-2-[(methylthio)methoxy]-5-(4-pyridin-2-ylphenyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate

A slurry of Example 2D (2.5 g, 3.55 mmol) in acetonitrile (70.0 mL) wastreated with dimethyl sulfide (6.6 mL, 89.2 mmol) at 25° C. followed bybenzoyl peroxide (3.4 g, 14.0 mmol), and the mixture was stirred at 25°C. for 15 minutes. The mixture was treated with additional benzoylperoxide (3.4 g, 14.0 mmol), and stirred for 1 hour at 25° C. Water wasadded and the mixture was partitioned between ethyl acetate and 10%Na₂CO₃. The organic phase was washed with brine, dried over MgSO₄,filtered, and the solvents were evaporated. The crude residue waspurified by silica gel chromatography eluting with a gradient startingwith dichloromethane and ending with 100% ethyl acetate to give thetitle compound (2.46 g, 91%).

EXAMPLE 204Bmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-bis(tert-butyl)-2,9,12-trioxo-5-[(phosphonooxy)methoxy]-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate

A solution of Example 204A (2.46 mg, 3.2 mmol) in tetrahydrofuran (16.0mL) was treated with 4 Å molecular sieves (8.0 g), a solution ofphosphoric acid (32.0 mL, 0.5 M in DMF), and N-iodosuccinimide (1.45 g,6.4 mmol) at 25° C. for 45 minutes. The mixture was poured into cold 10%sodium carbonate, diluted with methanol, filtered and through celite.The filtrate was decolorized with saturated sodium thiosulfate andconcentrated. The resulting concentrate was dissolved in methanol,filtered and concentrated. Methanol and water were added to theresulting concentrate and the pH was adjusted to 9 by addition of 10%Na₂CO₃, and the mixture was purified by reverse phase HPLC using a C18column, eluting with a gradient starting with water and ending withmethanol, to give the title compound as a disodium salt (1.53 g, 56%yield). ¹H NMR (300 MHz, MeOH-d₄), δ ppm 0.80 (s, 9 H), 0.88 (s, 9 H),1.67-1.76 (m, 1H), 2.00-2.10 (m, 1 H), 2.68-2.99 (m, 4 H), 3.54 (s, 3H), 3.65 (s, 3 H), 3.70-3.74 (m, 1 H), 3.93 (s, 1 H), 3.94 (s, 1 H),4.22-4.32 (m, 1 H), 4.34-4.38 (m, 1 H), 5.02 (dd, J=8.8, 5.5 Hz, 1 H),5.15 (dd, J=8.8, 5.2 Hz, 1 H), 7.05-7.33 (m, 8 H), 7.77-7.89 (m, 4 H),8.56 (m, 1 H).

EXAMPLE 205methyl(1S,4S,6S)-6-((1S)-1-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-2-phenylethyl)-1-tert-butyl-10,10-dihydroxy-8-methyl-10-oxido-2-oxo-4-(4-pyridin-2-ylbenzyl)-7,9-dioxa-3-aza-10-phosphadec-1-ylcarbamateEXAMPLE 205AN¹-[(1S,3S,4S)-4-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-3-[1-(ethylthio)ethoxy]-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]-N²-(methoxycarbonyl)-3-methyl-L-valinamide

To a solution of the compound of Example 111 (0.200 g, 0.248 mmol) andethyl sulfide (0.70 mL, 6.48 mmol) in acetonitrile (2.0 mL) at 0° C. wasadded benzoyl peroxide (0.38 g, 1.57 mmol) in three portions over 2hours. The reaction was diluted with ethyl acetate and washed with 10%Na₂CO₃ and brine. The organic was dried over MgSO₄, filtered andevaporated. The residue was chromatographed on silica gel eluting with agradient starting with dichloromethane and ending with ethyl acetate togive the title compound (0.210 g, 95% yield).

EXAMPLE 205Bmethyl(1S,4S,6S)-6-((1S)-1-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-2-phenylethyl)-1-tert-butyl-10,10-dihydroxy-8-methyl-10-oxido-2-oxo-4-(4-pyridin-2-ylbenzyl)-7,9-dioxa-3-aza-10-phosphadec-1-ylcarbamate

To a solution of the product from Example 205A (0.285 g, 0.319 mmol) inN,N-dimethylformamide (6.0 mL) at room temperature was added molecularsieves (4 Å, 1.20 g), and the reaction was cooled to 0° C. A solution ofphosphoric acid (0.100 g, 1.02 mmol) in N,N-dimethylformamide (5.0 mL)was added, followed by addition of N-iodosuccinimide (0.145 g, 0.644mmol), and the mixture was stirred at room temperature for 1 hour. Thereaction was diluted with methanol and filtered through celite. Thefiltrate was treated with Na₂S₂O₃ (saturated) and the pH was adjusted to9 with 10% Na₂CO₃. The methanol was evaporated and the mixture waspurified by chromatography using a C18 column, eluting with a gradientstarting with water and ending with methanol, to give the title compoundas the disodium salt (0.069 g, 22% yield). ¹H NMR (300 MHz, MeOH-d₄), δppm 0.79 (s, 9 H), 0.97, 1.01 (2s, 9 H), 1.49 (d, J=5.2 Hz, 1.5 H), 1.51(d, J=5.2 Hz, 1.5 H), 1.54-1.77 (m, 1H), 1.92-2.31 (m, 2 H), 2.63-3.02(m, 6 H), 3.12-3.21 (m, 1 H), 3.57, 3.59 (2s, 3 H), 3.99-4.03 (m, 2.5H), 4.17-4.21 (m, 0.5 H), 4.29-4.47 (m, 4 H), 5.39-5.46 (m, 0.5 H),5.46-5.53 (m, 0.5 H), 6.95-6.99 (m, 3 H), 7.06-7.12 (m, 2 H), 7.27-7.39(m, 8 H), 7.79-7.89, (m, 4 H), 8.56 (m, 1 H).

EXAMPLE 206methyl(1S,4S,5S)-4benzyl-1-tert-butyl-5-{(2S)-2-[((2S)-3,3-dimethyl-2-{3-[(6-methylpyridin-2-yl)methyl]-2-oxoimidazolidin-1-yl}butanoyl)amino]-3-phenylpropyl}-9,9-dihydroxy-9-oxido-2-oxo-6,8-dioxa-3-aza-9-phosphanon-1-ylcarbamateEXAMPLE 206AN¹-{(1S,2S,4S)-1-benzyl-4-[((2S)-3,3-dimethyl-2-{3-[(6-methylpyridin-2-yl)methyl]-2-oxoimidazolidin-1-yl}butanoyl)amino]-2-[(methylthio)methoxy]-5-phenylpentyl}-N²-(methoxycarbonyl)-3-methyl-L-valinamide

A solution containing the product of Example 10E (1.71 g, 2.3 mmol) inDMSO (3.3 g, 42.3 mmol) was treated with acetic acid (4.1 g, 69 mmol)and acetic anhydride (2.35 g, 23 mmol) at 25° C. for 3 days. Excess icewas added to the mixture which was then made alkaline with 10% sodiumcarbonate. The mixture was extracted with ethyl acetate, the organiclayer was separated, washed with 10% sodium carbonate, water (3×),brine, and dried over sodium sulfate. The solvents were evaporated, andthe product was purified by chromatography on silica gel eluting with30-100% ethyl acetate/dichloromethane to give the title compound (1.1 g,60% yield).

EXAMPLE 206Bmethyl(1S,4S,5S)-4-benzyl-1-tert-butyl-5-{(2S)-2-[((2S)-3,3-dimethyl-2-{3-[((6-methylpyridin-2-yl)methyl]-2-oxoimidazolidin-1-yl}butanoyl)amino]-3-phenylpropyl}-9,9-dihydroxy-9-oxido-2-oxo-6,8-dioxa-3-aza-9-phosphanon-1-ylcarbamate

A mixture of Example 206A, phosphoric acid (0.85 g, 8.6 mmol), andmolecular sieves (4A, 6 g) in N,N-dimethylformamide (28 mL) at 0° C. wastreated with NIS (0.41 g, 1.78 mmol) for 3 h. The mixture was filtered,the solids washed with methanol, and the resultant filtrant was treatedwith sodium sulfite until colorless and made alkaline with 10% sodiumcarbonate to pH 9. The mixture was refiltered, and the solvents wereevaporated. The residue was triturated with methanol, filtered, and thesolvents were evaporated. The crude residue was purified bychromatography on silica gel eluting with (reverse phase) 100%water-100% methanol to give the title compound as the disodium salt(0.68 g, 55% yield). ¹H NMR (300 MHz, MeOD-d₄) δ ppm 0.84-0.93 (m, 9 H),0.95 (s, 9 H), 1.61-1.87 (m, 1 H), 1.97-2.14 (m, 1 H), 2.39-2.49 (m, 2H), 2.54 (s, 3 H), 2.75 (s, 1 H), 2.77-2.82 (m, 1 H), 2.86 (d, J=5.15Hz, 1 H), 2.90-2.98 (m, 1 H), 2.98-3.08 (m, 1 H), 3.13 (q, J=8.82 Hz, 1H), 3.34-3.36 (m, 2 H), 3.66 (s, 3 H), 3.70 (s, 1 H), 3.98 (s, 1 H),4.10 (s, 1 H), 4.38 (s, 1 H), 4.44 (d, J=5.15 Hz, 2 H), 4.56 (s, 1 H),5.03 (dd, J=9.38, 5.33 Hz, 1 H), 5.18 (dd, J=8.82, 5.52 Hz, 1 H),6.98-7.31 (m, 12 H), 7.72 (t, J=7.72 Hz, 1 H).

EXAMPLE 207methyl(1S,4S,5S,7S,10S)-4benzyl-1,10-bis(tert-butyl)-2,9,12-trioxo-5-[1-(phosphonooxy)ethoxy]-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamateEXAMPLE 207Amethyl(1S)-1-({[(1S,2S,4S)-1-benzyl-2-[1-(ethylthio)ethoxy]-4-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-5-(4-pyridin-2-ylphenyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate

To a slurry of the compound of Example 2D (2.00 g, 2.84 mmol) and ethylsulfide (8.0 mL, 74.06 mmol) in acetonitrile (28.0 mL) at roomtemperature was added benzoyl peroxide (4.95 g, 20.45 mmol) in threeportions over 2 hours. The reaction was diluted with ethyl acetate andwashed with 10% Na₂CO₃ and brine. The organic was dried over MgSO₄,filtered and evaporated. The residue was chromatographed on silica geleluting with a gradient starting with dichloromethane and ending withethyl acetate to give the title compound (2.35 g, 84% yield).

EXAMPLE 207Bmethyl(1S,4S,5S,7S,10S)-4-benzyl-1,10-bis(tert-butyl)-2,9,12-trioxo-5-[1-(phosphonooxy)ethoxy]-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate

To a slurry of the product from Example 207A (1.10 g, 1.39 mmol) andmolecular sieves (4 Å, 3.5 g), in N,N-dimethylformamide (7.0 mL) at 0°C. were added a solution of phosphoric acid in N,N-dimethylformamide(13.0 mL, 0.5 M) and N-iodosuccinimide (0.626 g, 2.78 mmol), and themixture was stirred at 0° C. for 4 hours. The reaction was treated withNa₂S₂O₃ (saturated) and the pH was adjusted to 9 with 10% Na₂CO₃. Themixture was diluted with methanol and filtered through celite Themethanol was evaporated and the mixture was purified by chromatographyusing a C18 column, eluting with a gradient starting with water andending with methanol, to give the title compound as the disodium salt(0.70 g, 58% yield). ¹H NMR (300 MHz, MeOH-d₄), δ ppm 0.69 (s, 9 H),0.93, 1.00 (2s, 9 H), 1.44 (d, J=5.2 Hz, 1.5 H), 1.47 (d, J=4.8 Hz, 1.5H), 1.52-1.76 (m, 1H), 1.95-2.05 (m, 0.5 H), 2.30-2.40 (m, 0.5 H),2.76-2.91 (m, 4 H), 3.58, 3.60 (2s, 3 H), 3.64 (s, 3 H), 3.84, 3.87 (2s,1 H), 3.89-3.97 (m, 0.5 H), 4.03, 4.06 (2s, 1 H), 4.14-4.37 (m, 2.5 H),5.34-5.41 (m, 0.5 H), 5.43-5.50 (m, 0.5 H), 7.02-7.19 (m, 5 H),7.28-7.37 (m, 3 H), 7.77-7.89, (m, 4 H), 8.57 (m, 1 H).

EXAMPLE 208methyl(1S)-3-amino-1-({[(1S,2S,4S)-1-benzyl-2-hydroxy-4-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-5-(4-pyridin-2-ylphenyl)pentyl]amino}carbonyl)-2,2-dimethyl-3-oxopropylcarbamateEXAMPLE 208Amethyl(3S)-3-[(tert-butoxycarbonyl)amino]-3-carboxy-2,2-dimethylpropanoate

Example 184A (100 mg, 0.21 mmol) was dissolved in dichloromethane (2 mL)and cooled to 0° C. Trifluoroacetic acid (2 mL) was added and thesolution was stirred at 0° C. for 1 hour. The ice bath was removed andthe solution was allowed to warm to ambient temperature over 3 hours.The solution was concentrated, toluene (5 mL) was added and the solutionconcentrated again. The residue was placed under vacuum for 2 hours,dissolved in dioxane (4 mL) and 10% sodium bicarbonate (1 mL). Withstirring, di-tert-butyl dicarbonate (93 mg, 0.42 mmol) was added and thesolution was stirred for 18 hours, the solution was concentrated and theresidue distributed between ether (10 mL) and H₂O (10 mL). Hydrochloricacid (1 mL, 0.5 M) was added and the aqueous layer was extracted withether (3 times 10 mL), the organic extracts combined and washed with H₂O(10 mL), dried (Na₂SO₄), filtered and the filtrate concentrated. Theresidue was purified by column chromatography on silica gel (10%methanol/chloroform) to yield a tan solid.

EXAMPLE 208B methylN¹-[(1S,2S,4S)-1-benzyl-2-hydroxy-4-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-5-(4-pyridin-2-ylphenyl)pentyl]-N²-(tert-butoxycarbonyl)-3,3-dimethyl-L-asparaginate

Example 208A (0.21 mmol) was dissolved in tetrahydrofuran (1 mL) and theproduct from Example 2C (114 mg, 0.21 mmol), diisopropylethylamine (111uL, 0.64 mmol) and3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (127 mg, 0.42mmol) were added. The solution was stirred at ambient temperature for 3hours. 10% Na₂CO₃ (5 mL) was added and stirring was continued for 20minutes. H₂O (5 mL) was added and the solution extracted with ethylacetate (3 times 10 mL), the organic extracts combined, washed with 10%Na₂CO₃ (10 mL) and saturated brine solution (10 mL), dried (Na₂SO₄),filtered and concentrated. The residue was purified by columnchromatography on silica gel (5% CH₃OH/CHCl₃) to yield a white solid(138 mg, 82%).

EXAMPLE 208Cmethyl(1S)-3-amino-1-({[(1S,2S,4S)-1-benzyl-2-hydroxy-4-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-5-(4-pyridin-2-ylphenyl)pentyl]amino}carbonyl)-2,2-dimethyl-3-oxopropylcarbamate

To Example 208B (56 mg, 0.07 mmol) were added dioxane (1 mL) and LiOH(0.28 mL, 0.5 M in H₂O) and the mixture was stirred for 1 hour atambient temperature and followed by the addition of HCl (0.5 mL, 1.0 N)and H₂O (3 mL). The mixture was extract with ethyl acetate (3 times 5mL) and the combined ethyl acetate extracts were dried (Na₂SO₄),filtered and concentrated. The crude residue (19 mg, 0.024 mmol) wasdissolved in dioxane (1 mL) and to this solution was added ammonia (61μL, 2M in methanol) followed by N-hydroxybenzotriazole (5 mg, 0.037mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (7 mg, 0.0.037mmol) and stirring was continued at ambient temperature for 4 hours. Thesolution was concentrated and the crude residue was dissolved indichloromethane (1 mL) and trifluoroacetic acid (1 mL) was added. Theresulting mixture was stirred at ambient temperature for 1 hour. Thesolution was concentrated and toluene (5 mL) was added and the solutionconcentrated again. The residue was placed under vacuum for 2 hours thendissolved in dioxane (1 mL) and to this solution was added sodiumhydroxide (27 μL, 3N) and methyl chloroformate (5 μL, 0.037 mmol). Themixture was stirred at 60° C. for 18 hours, cooled to ambienttemperature and concentrated. The crude residue was purified on apreparative TLC plate (silica gel, 20×20 cm, 5% methanol/chloroform) togive a solid white product (7 mg, 39%); ¹H NMR (d₆-DMSO) δ 8.64 (d, 1H),7.97-7.30 (m, 6H), 7.35-6.82 (m, 6H), 6.71-6.57 (t, 1H), 4.85-4.75 (m,1H), 4.23-4.05 (m, 2H), 3.87-3.76 (d, 1H), 3.50 (s, 3H), 3.31 (s, 3H),2.85-2.63 (m, 4H), 1.70-1.36 (m, 4H), 1.23 (s, 3H), 1.04 (s, 3H), 0.80(s, 9H).

The following additional compounds of the present invention can beprepared by one skilled in the art using known synthetic methodology orby using synthetic methodology described in the Schemes and Examplescontained herein. The additional compounds encompassed by the followingtables can be described by taking one core from Table 1, one R¹substituent from Table 2, one R² substituent from Table 3, one R³substituent from Table 4, one R⁶ substituent from Table 5, one R⁷substituent from Table 6, and one R⁸ substituent from Table 7, one R⁹substituent from Table 8, or one R¹¹ substituent from Table 9; whereinX₁ in the tables of substituents represents the Core Ring Structure.

TABLE 1 Examples of Core Ring Structures

1

2

2

4

5

6

TABLE 2 Examples of R¹ Substituents X₁—CH₃

1 2 3 4

5 6 7 8

TABLE 3 Examples of R² Substituents X₁—H X₁—CH₃

1 2 3 4

5 6 7 8

9 10 11 12

13 14 15 16

17 18 19 20

TABLE 4 Examples of R³ Substituents

1 2 3

4 5

6 7

8 9 10

11 12 13

14 15 16

17 18 19 20

TABLE 5 Examples of R⁶ Substituents

1 2 3

4 5

6 7

8 9 10

11 12 13

14 15 16 17

18 19 20

TABLE 6 Examples of R⁷ Substituents X₁—H X₁—CH₃

1 2 3 4 5

6 7 8 9

10 11 12 13 14

15 16 17 18 19 20

TABLE 7 Examples of R⁸ Substituents X₁—OCH₃

1 2 3 4

5 6

7 8

TABLE 8 Examples of R⁹ Substituents

1 2

3 4

5 6

7 8

9 10

11 12

13 14

15 16

17 18

19 20

21 22

23 24

25 26

27 28

TABLE 9 Examples of R¹¹ Substituents

1 2

3 4

5 6

7 8

9 10

11 12

13 14

15 16

17 18

19 20

21 22

23 24

25 26

27 28

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

1. A compound having formula (III)

or a pharmaceutically acceptable salt form or a stereoisomer thereof,wherein: B is H or —CH₂R⁹; L is —C(═O), —C(═S), —C(═NH) or —S(O)₂; R¹ isalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl orheteroaryl; wherein each R¹ is substituted with 0, 1 or 2 substituentsindependently selected from the group consisting of cyano, halo, nitro,oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),—N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,—N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),—N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂, —C(O)N(H)(alkyl),—C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH₂,-alkylN(H)(alkyl), -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂,-alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH,-alkylC(O)Oalkyl, -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl),-alkylC(O)N(alkyl)₂, and R^(1a); R^(1a) is cycloalkyl, cycloalkenyl,heterocycle, aryl or heteroaryl; wherein each R^(1a) is substituted with0, 1, 2, 3 or 4 substituents independently selected from the groupconsisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy,alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),—N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),—N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂, —C(O)N(H)(alkyl),—C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH₂,-alkylN(H)(alkyl), -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂,-alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH,-alkylC(O)Oalkyl, -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and-alkylC(O)N(alkyl)₂; R² is alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each R² issubstituted with 0, 1 or 2 substituents independently selected from thegroup consisting of halo, —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a),—NR_(a)R_(b), —NR_(b)C(O)R_(a) —N(R_(b))C(O)OR_(a),—N(R_(a))C(═N)NR_(a)R_(b), —N(R_(a))C(O)NR_(a)R_(b), —C(O)NR_(a)R_(b),—C(O)OR_(a) and R^(2a); R^(2a) is cycloalkyl, cycloalkenyl, heterocycle,aryl or heteroaryl; wherein each R^(2a) is substituted with 0, 1, 2, 3or 4 substituents independently selected from the group consisting ofcyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,—N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,—N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),—N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂, —C(O)N(H)(alkyl),—C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH₂,-alkylN(H)(alkyl), -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂,-alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH,-alkylC(O)Oalkyl, -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and-alkyl-C(O)N(alkyl)₂; R³ is alkyl, alkenyl, alkynyl, haloalkyl,haloalkenyl, -alkylOR_(a), -alkylSR_(a), -alkylSOR_(a), -alkylSO₂R_(a),-alkylNR_(a)R_(b), -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)OR_(a),-alkylN(R_(a))C(═N)NR_(a)R_(b), -alkylN(R_(a))C(O)NR_(a)R_(b),-alkylC(O)NR_(a)R_(b), -alkylC(O)OR_(a), cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkenylalkyl, heterocycle, heterocyclealkyl, aryl,arylalkyl, heteroaryl or heteroarylalkyl; wherein the cycloalkyl,cycloalkenyl, heterocycle, aryl, heteroaryl, cycloalkyl moiety of thecycloalkylalkyl, cycloalkenyl moiety of the cycloalkenylalkyl,heterocycle moiety of the heterocyclealkyl, heteroaryl moiety of theheteroarylalkyl and the aryl moiety of the arylalkyl are independentlysubstituted with 0, 1, 2, 3 or 4 substituents independently selectedfrom the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl,alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH,—S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl,—N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH,—C(O)Oalkyl, —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl,hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),-alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),-alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl, -alkylC(O)NH₂,-alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and R^(3a); R^(3a) iscycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein eachR^(3a) is substituted with 0, 1, 2, 3 or 4 substituents independentlyselected from the group consisting of cyano, halo, oxo, alkyl, alkenyl,hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),—SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,—N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,—C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,-alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl)₂,-alkylC(O)OH, -alkylC(O)Oalkyl, -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl),and -alkylC(O)N(alkyl)₂; R⁴ is H and R⁵ is OR¹⁶; R⁶ is alkyl, alkenyl,alkynyl, haloalkyl, haloalkenyl, -alkylOR_(a), -alkylSR_(a),-alkylSOR_(a), -alkylSO₂R_(a), -alkylNR_(a)R_(b),-alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)OR_(a),-alkylN(R_(a))C(═N)NR_(a)R_(b), -alkylN(R_(a))C(O)NR_(a)R_(b),-alkylC(O)NR_(a)R_(b), -alkylC(O)OR_(a), cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkenylalkyl, heterocycle, heterocyclealkyl, aryl,arylalkyl, heteroaryl or heteroarylalkyl; wherein the cycloalkyl,cycloalkenyl, heterocycle, aryl, heteroaryl, cycloalkyl moiety of thecycloalkylalkyl, cycloalkenyl moiety of the cycloalkenylalkyl,heterocycle moiety of the heterocyclealkyl, heteroaryl moiety of theheteroarylalkyl and the aryl moiety of the arylalkyl are independentlysubstituted with 0, 1, 2, 3 or 4 substituents independently selectedfrom the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl,alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH,—S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl,—N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH,—C(O)Oalkyl, —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl,hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),-alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),-alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl, -alkylC(O)NH₂,-alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and R^(6a); R^(6a) iscycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein eachR^(6a) is substituted with 0, 1, 2, 3 or 4 substituents independentlyselected from the group consisting of cyano, halo, oxo, alkyl, alkenyl,hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),—SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,—N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,—C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,-alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl)₂,-alkylC(O)OH, -alkylC(O)Oalkyl, -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl),and -alkylC(O)N(alkyl)₂; R⁷ is —N(R_(b))C(O)OR_(a), alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,heterocycle, aryl and heteroaryl are independently substituted with 0, 1or 2 substituents independently selected from the group consisting ofhalo, —OR_(a), —OC(O)R_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —NR_(a)R_(b),—N(R_(b))C(O)R_(a), —N(R_(b))C(O)OR_(a), —N(R_(a))C(═N)NR_(a)R_(b),—N(R_(a))C(O)NR_(a)R_(b), —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(7a);R^(7a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;wherein each R^(7a) is substituted with 0, 1, 2, 3 or 4 substituentsindependently selected from the group consisting of cyano, halo, nitro,oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),—N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,—N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),—N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂, —C(O)N(H)(alkyl),—C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH₂,-alkylN(H)(alkyl), -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂,-alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH,-alkylC(O)Oalkyl, -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and-alkyl-C(O)N(alkyl)₂; R⁹ is alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl or heterocycle; wherein each R⁹ issubstituted with 0, 1, 2 or 3 substituents independently selected fromthe group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, halo,nitro, oxo, —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a),—SO₂NR_(a),—SO₂OR_(a), —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))SO₂R_(a),—N(R_(b))SO₂NR_(a)R_(b), —N(R_(b))C(O)NR_(a)R_(b), —N(R_(b))C(O)OR_(a),—C(O)R_(a), —C(O)NR_(a)R_(b), —C(O)OR_(a), haloalkyl, nitroalkyl,cynaoalkyl, formylalkyl, -alkylOR_(a), -alkyl-O—P(O)(OR_(a))(OR_(a)),-alkylNR_(a)R_(b), -alkylN(R_(b))C(O)OR_(a),-alkylN(R_(b))SO₂NR_(a)R_(b), -alkylN(R_(b))C(O)R_(a),-alkylN(R_(b))C(O)NR_(a)R_(b), -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a),-alkylC(O)R_(a), -alkylC(O)NR_(a)R_(b) and R^(9a); R^(9a) is cycloalkyl,cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each R^(9a) issubstituted with 0, 1, 2, 3 or 4 substituents independently selectedfrom the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl,alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH,—S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl,—N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH,—C(O)Oalkyl, —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl,haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),-alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),-alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl, -alkylC(O)NH₂,-alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂; R¹⁶ is hydrogen or R¹⁵;R¹⁵ is

R₁₀₃ is C(R₁₀₅)₂, O or —N(R₁₀₅); R₁₀₄ is hydrogen, alkyl, haloalkyl,alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl ordialkylaminocarbonyl, each M is independently selected from the groupconsisting of H, —N(R₁₀₅)₂, alkyl, alkenyl, and R₁₀₆; wherein 1 to 4—CH₂ radicals of the alkyl or alkenyl, other than the —CH₂ radical thatis bound to Z, is optionally replaced by a heteroatom group selectedfrom the group consisting of O, S, S(O), SO₂ and N(R₁₀₅); and whereinany hydrogen in said alkyl, alkenyl or R₁₀₆ is optionally replaced witha substituent selected from the group consisting of oxo, —OR₁₀₅, —R₁₀₅,—N(R₁₀₅)₂, —CN, —C(O)OR₁₀₅, —C(O)N(R₁₀₅)₂, —SO₂N(R₁₀₅),—N(R₁₀₅)C(O)R₁₀₅, —C(O)R₁₀₅, —SR₁₀₅, —S(O)R₁₀₅, —SO₂R₁₀₅, —OCF₃, —SR₁₀₆,—SOR₁₀₆, —SO₂R₁₀₆, —N(R₁₀₅)SO₂R₁₀₅, halo, —CF₃, NO₂ and phenyl; providedthat when M is —N(R₁₀₅)₂, Z₁ and Z₂ are —CH₂; Z₁ is CH₂, O, S, —N(R₁₀₅),or, when M is absent, H; Z₂ is CH₂, O, S or —N(R₁₀₅); Q is O or S; W isP or S; wherein when W is S, Z₁ and Z₂ are not S; M′ is H, alkyl,alkenyl or R₁₀₆; wherein 1 to 4 —CH₂ radicals of the alkyl or alkenyl isoptionally replaced by a heteroatom group selected from O, S, S(O), SO₂,or N(R₁₀₅); and wherein any hydrogen in said alkyl, alkenyl or R₁₀₆ isoptionally replaced with a substituent selected from the groupconsisting of oxo, —OR₁₀₅, —R₁₀₅, —N(R₁₀₅)₂, —CN, —C(O)OR₁₀₅,—C(O)N(R₁₀₅)₂, —SO₂N(R₁₀₅), —N(R₁₀₅)C(O)R₁₀₅, —C(O)R₁₀₅, —SR₁₀₅,—S(O)R₁₀₅, —SO₂R₁₀₅, —OCF₃, —SR₁₀₆, —SOR₁₀₆, —SO₂R₁₀₆, —N(R₁₀₅)SO₂R₁₀₅,halo, —CF₃ and NO₂; R₁₀₆ is a monocyclic or bicyclic ring systemselected from the group consisting of aryl, cycloalkyl, cycloalkenylheteroaryl and heterocycle; wherein any of said heteroaryl andheterocycle ring systems contains one or more heteroatoms selected fromthe group consisting of O, N, S, SO, SO₂ and N(R₁₀₅); and wherein any ofsaid ring system is substituted with 0, 1, 2, 3, 4, 5 or 6 substituentsselected from the group consisting of hydroxy, alkyl, alkoxy, and—OC(O)alkyl; each R₁₀₅ is independently selected from the groupconsisting of H or alkyl; wherein said alkyl is optionally substitutedwith a ring system selected from the group consisting of aryl,cycloalkyl, cycloalkenyl, heteroaryl and heterocycle; wherein any ofsaid heteroaryl and heterocycle ring systems contains one or moreheteroatoms selected from the group consisting of O, N, S, SO, SO₂, andN(R₁₀₅); and wherein any one of said ring systems is substituted with 0,1, 2, 3 or 4 substituents selected from the group consisting of oxo,—OR₁₀₅, —R₁₀₅, —N(R₁₀₅)₂, —N(R₁₀₅)C(O)R₁₀₅, —CN, —C(O)OR₁₀₅,—C(O)N(R₁₀₅)₂, halo and —CF₃; each R₁₀₇ and R₁₀₈ are independentlyselected from the group consisting of hydrogen and alkyl; q is 0 or 1; mis 0 or 1; m′ is 0 or 1; m″ is 0 or 1; r is 0, 1, 2, 3 or 4; t is 0 or1; R_(a) and R_(b) at each occurrence are independently selected fromthe group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,aryl, heteroaryl and heterocycle; wherein each R_(a) and R_(b), at eachoccurrence, is independently substituted with 0, 1, 2 or 3 substituentsindependently selected from the group consisting of cyano, nitro, halo,oxo, hydroxy, alkoxy, alkyl, alkenyl, alkynyl, —NH₂, —N(H)(alkyl),—N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,—N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),—N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂, —C(O)N(H)(alkyl),—C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH₂,-alkylN(H)(alkyl), -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂,-alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH,-alkylC(O)Oalkyl, -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl),-alkylC(O)N(alkyl)₂ and R_(c); alternatively, R_(a) and R_(b), togetherwith the nitrogen atom to which they are attached, form a ring selectedfrom the group consisting of heteroaryl and heterocycle; wherein each ofthe heteroaryl and heterocycle is independently substituted with 0, 1, 2or 3 substituents independently selected from the group consisting ofalkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo, hydroxy,alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),—N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),—N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂, —C(O)N(H)(alkyl),—C(O)N(alkyl)₂, cyanoalkyl, formylalkyl, nitroalkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),-alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),-alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl, -alkylC(O)NH₂,-alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and R_(c); R_(c) is aryl,heteroaryl or heterocycle; wherein each R_(c) is independentlysubstituted with 0, 1, 2, 3 or 4 substituents independently selectedfrom the group consisting of halo, nitro, oxo, alkyl, alkenyl, alkynyl,hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),—SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,—N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,—C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,alkoxyalkyl, -alkyl-NH₂, -alkyl-N(H)(alkyl), -alkyl-N(alkyl)₂,-alkyl-N(H)C(O)NH₂, -alkyl-N(H)C(O)N(H)(alkyl),-alkyl-N(H)C(O)N(alkyl)₂, -alkyl-C(O)OH, -alkyl-C(O)Oalkyl,-alkyl-C(O)NH₂, -alkyl-C(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂; and nis 1 or
 2. 2. A compound having formula (III)

or a pharmaceutically acceptable salt form or a stereoisomer thereof,wherein: B is H or —CH₂R⁹; L is —C(═O), —C(═S), —C(═NH) or —S(O)₂; R¹ isalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl orheteroaryl; wherein each R¹ is substituted with 0, 1 or 2 substituentsindependently selected from the group consisting of cyano, halo, nitro,oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),—N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,—N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),—N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂, —C(O)N(H)(alkyl),—C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH₂,-alkylN(H)(alkyl), -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂,-alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH,-alkylC(O)Oalkyl, -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl),-alkylC(O)N(alkyl)₂, and R^(1a); R^(1a) is cycloalkyl, cycloalkenyl,heterocycle, aryl or heteroaryl; wherein each R^(1a) is substituted with0, 1, 2, 3 or 4 substituents independently selected from the groupconsisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy,alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),—N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),—N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂, —C(O)N(H)(alkyl),—C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH₂,-alkylN(H)(alkyl), -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂,-alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH,-alkylC(O)Oalkyl, -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and-alkylC(O)N(alkyl)₂; R² is alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each R² issubstituted with 0, 1 or 2 substituents independently selected from thegroup consisting of halo, —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a),—NR_(a)R_(b), —NR_(b)C(O)R_(a) —N(R_(b))C(O)OR_(a),—N(R_(a))C(═N)NR_(a)R_(b), —N(R_(a))C(O)NR_(a)R_(b), —C(O)NR_(a)R_(b),—C(O)OR_(a) and R^(2a); R^(2a) is cycloalkyl, cycloalkenyl, heterocycle,aryl or heteroaryl; wherein each R^(2a) is substituted with 0, 1, 2, 3or 4 substituents independently selected from the group consisting ofcyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂,—N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,—N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),—N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂, —C(O)N(H)(alkyl),—C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH₂,-alkylN(H)(alkyl), -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂,-alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH,-alkylC(O)Oalkyl, -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and-alkyl-C(O)N(alkyl)₂; R³ is alkyl, alkenyl, alkynyl, haloalkyl,haloalkenyl, -alkylOR_(a), -alkylSR_(a), -alkylSOR_(a), -alkylSO₂R_(a),-alkylNR_(a)R_(b), -alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)OR_(a),-alkylN(R_(a))C(═N)NR_(a)R_(b), -alkylN(R_(a))C(O)NR_(a)R_(b),-alkylC(O)NR_(a)R_(b), -alkylC(O)OR_(a), cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkenylalkyl, heterocycle, heterocyclealkyl, aryl,arylalkyl, heteroaryl or heteroarylalkyl; wherein the cycloalkyl,cycloalkenyl, heterocycle, aryl, heteroaryl, cycloalkyl moiety of thecycloalkylalkyl, cycloalkenyl moiety of the cycloalkenylalkyl,heterocycle moiety of the heterocyclealkyl, heteroaryl moiety of theheteroarylalkyl and the aryl moiety of the arylalkyl are independentlysubstituted with 0, 1, 2, 3 or 4 substituents independently selectedfrom the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl,alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH,—S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl,—N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH,—C(O)Oalkyl, —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl,hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),-alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),-alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl, -alkylC(O)NH₂,-alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and R^(3a); R^(3a) iscycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein eachR^(3a) is substituted with 0, 1, 2, 3 or 4 substituents independentlyselected from the group consisting of cyano, halo, oxo, alkyl, alkenyl,hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),—SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,—N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,—C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,-alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl)₂,-alkylC(O)OH, -alkylC(O)Oalkyl, -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl),and -alkylC(O)N(alkyl)₂; R⁵ is H and R⁴ is OR¹⁶; R⁶ is alkyl, alkenyl,alkynyl, haloalkyl, haloalkenyl, -alkylOR_(a), -alkylSR_(a),-alkylSOR_(a), -alkylSO₂R_(a), -alkylNR_(a)R_(b),-alkylN(R_(b))C(O)R_(a), -alkylN(R_(b))C(O)OR_(a),-alkylN(R_(a))C(═N)NR_(a)R_(b), -alkylN(R_(a))C(O)NR_(a)R_(b),-alkylC(O)NR_(a)R_(b), -alkylC(O)OR_(a), cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkenylalkyl, heterocycle, heterocyclealkyl, aryl,arylalkyl, heteroaryl or heteroarylalkyl; wherein the cycloalkyl,cycloalkenyl, heterocycle, aryl, heteroaryl, cycloalkyl moiety of thecycloalkylalkyl, cycloalkenyl moiety of the cycloalkenylalkyl,heterocycle moiety of the heterocyclealkyl, heteroaryl moiety of theheteroarylalkyl and the aryl moiety of the arylalkyl are independentlysubstituted with 0, 1, 2, 3 or 4 substituents independently selectedfrom the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl,alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH,—S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl,—N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH,—C(O)Oalkyl, —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl,hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),-alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),-alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl, -alkylC(O)NH₂,-alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and R^(6a); R^(6a) iscycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein eachR^(6a) is substituted with 0, 1, 2, 3 or 4 substituents independentlyselected from the group consisting of cyano, halo, oxo, alkyl, alkenyl,hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),—SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,—N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,—C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl), -alkylN(alkyl)₂,-alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl)₂,-alkylC(O)OH, -alkylC(O)Oalkyl, -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl),and -alkylC(O)N(alkyl)₂; R⁷ is —N(R_(b))C(O)OR_(a), alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,heterocycle, aryl and heteroaryl are independently substituted with 0, 1or 2 substituents independently selected from the group consisting ofhalo, —OR_(a), —OC(O)R_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —NR_(a)R_(b),—N(R_(b))C(O)R_(a), —N(R_(b))C(O)OR_(a), —N(R_(a))C(═N)NR_(a)R_(b),—N(R_(a))C(O)NR_(a)R_(b), —C(O)NR_(a)R_(b), —C(O)OR_(a) and R^(7a);R^(7a) is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl;wherein each R^(7a) is substituted with 0, 1, 2, 3 or 4 substituentsindependently selected from the group consisting of cyano, halo, nitro,oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl),—N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,—N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),—N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂, —C(O)N(H)(alkyl),—C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH₂,-alkylN(H)(alkyl), -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂,-alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH,-alkylC(O)0alkyl, -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl) and-alkyl-C(O)N(alkyl)₂; R⁹ is alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl or heterocycle; wherein each R⁹ issubstituted with 0, 1, 2 or 3 substituents independently selected fromthe group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, halo,nitro, oxo, —OR_(a), —SR_(a), —SOR_(a), —SO₂R_(a), —SO₂NR_(a),—SO₂OR_(a), —NR_(a)R_(b), —N(R_(b))C(O)R_(a), —N(R_(b))SO₂R_(a),—N(R_(b))SO₂NR_(a)R_(b), —N(R_(b))C(O)NR_(a)R_(b), —N(R_(b))C(O)OR_(a),—C(O)R_(a), —C(O)NR_(a)R_(b), —C(O)OR_(a), haloalkyl, nitroalkyl,cynaoalkyl, formylalkyl, -alkylOR_(a), -alkyl-O—P(O)(OR_(a))(OR_(a)),-alkylNR_(a)R_(b), -alkylN(R_(b))C(O)OR_(a),-alkylN(R_(b))SO₂NR_(a)R_(b), -alkylN(R_(b))C(O)R_(a),-alkylN(R_(b))C(O)NR_(a)R_(b), -alkylN(R_(b))SO₂R_(a), -alkylC(O)OR_(a),-alkylC(O)R_(a), -alkylC(O)NR_(a)R_(b) and R^(9a); R^(9a) is cycloalkyl,cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each R^(9a) issubstituted with 0, 1, 2, 3 or 4 substituents independently selectedfrom the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl,alkynyl, hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH,—S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl,—N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH,—C(O)Oalkyl, —C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, cyanoalkyl,haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),-alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),-alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl, -alkylC(O)NH₂,-alkylC(O)N(H)(alkyl) and -alkylC(O)N(alkyl)₂; R¹⁶ is hydrogen or R¹⁵;R¹⁵ is

R₁₀₃ is C(R₁₀₅)₂, O or —N(R₁₀₅); R₁₀₄ is hydrogen, alkyl, haloalkyl,alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl ordialkylaminocarbonyl, each M is independently selected from the groupconsisting of H, —N(R₁₀₅)₂, alkyl, alkenyl, and R₁₀₆; wherein 1 to 4—CH₂ radicals of the alkyl or alkenyl, other than the —CH₂ radical thatis bound to Z, is optionally replaced by a heteroatom group selectedfrom the group consisting of O, S, S(O), SO₂ and N(R₁₀₅); and whereinany hydrogen in said alkyl, alkenyl or R₁₀₆ is optionally replaced witha substituent selected from the group consisting of oxo, —OR₁₀₅, —R₁₀₅,—N(R₁₀₅)₂, —CN, —C(O)OR₁₀₅, —C(O)N(R₁₀₅)₂, —SO₂N(R₁₀₅),—N(R₁₀₅)C(O)R₁₀₅, —C(O)R₁₀₅, —SR₁₀₅, —S(O)R₁₀₅, —SO₂R₁₀₅, —OCF₃, —SR₁₀₆,—SOR₁₀₆, —SO₂R₁₀₆, —N(R₁₀₅)SO₂R₁₀₅, halo, —CF₃, NO₂ and phenyl; providedthat when M is —N(R₁₀₅)₂, Z₁ and Z₂ are —CH₂; Z₁ is CH₂, O, S, —N(R₁₀₅),or, when M is absent, H; Z₂ is CH₂, O, S or —N(R₁₀₅); Q is O or S; W isP or S; wherein when W is S, Z₁ and Z₂ are not S; M′ is H, alkyl,alkenyl or R₁₀₆; wherein 1 to 4 —CH₂ radicals of the alkyl or alkenyl isoptionally replaced by a heteroatom group selected from O, S, S(O), SO₂,or N(R₁₀₅); and wherein any hydrogen in said alkyl, alkenyl or R₁₀₆ isoptionally replaced with a substituent selected from the groupconsisting of oxo, —OR₁₀₅, —R₁₀₅, —N(R₁₀₅)₂, —CN, —C(O)OR₁₀₅,—C(O)N(R₁₀₅)₂, —SO₂N(R₁₀₅), —N(R₁₀₅)C(O)R₁₀₅, —C(O)R₁₀₅, —SR₁₀₅,—S(O)R₁₀₅, —SO₂R₁₀₅, —OCF₃, —SR₁₀₆, —SOR₁₀₆, —SO₂R₁₀₆, —N(R₁₀₅)SO₂R₁₀₅,halo, —CF₃ and NO₂; R₁₀₆ is a monocyclic or bicyclic ring systemselected from the group consisting of aryl, cycloalkyl, cycloalkenylheteroaryl and heterocycle; wherein any of said heteroaryl andheterocycle ring systems contains one or more heteroatoms selected fromthe group consisting of O, N, S, SO, SO₂ and N(R₁₀₅); and wherein any ofsaid ring system is substituted with 0, 1, 2, 3, 4, 5 or 6 substituentsselected from the group consisting of hydroxy, alkyl, alkoxy, and—OC(O)alkyl; each R₁₀₅ is independently selected from the groupconsisting of H or alkyl; wherein said alkyl is optionally substitutedwith a ring system selected from the group consisting of aryl,cycloalkyl, cycloalkenyl, heteroaryl and heterocycle; wherein any ofsaid heteroaryl and heterocycle ring systems contains one or moreheteroatoms selected from the group consisting of O, N, S, SO, SO₂, andN(R₁₀₅); and wherein any one of said ring systems is substituted with 0,1, 2, 3 or 4 substituents selected from the group consisting of oxo,—OR₁₀₅, —R₁₀₅, —N(R₁₀₅)₂, —N(R₁₀₅)C(O)R₁₀₅, —CN, —C(O)OR₁₀₅,—C(O)N(R₁₀₅)₂, halo and —CF₃; each R₁₀₇ and R₁₀₈ are independentlyselected from the group consisting of hydrogen and alkyl; q is 0 or 1; mis 0 or 1; m′ is 0 or 1; m″ is 0 or 1; r is 0, 1, 2, 3 or 4; t is 0 or1; R_(a) and R_(b) at each occurrence are independently selected fromthe group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,aryl, heteroaryl and heterocycle; wherein each R_(a) and R_(b), at eachoccurrence, is independently substituted with 0, 1, 2 or 3 substituentsindependently selected from the group consisting of cyano, nitro, halo,oxo, hydroxy, alkoxy, alkyl, alkenyl, alkynyl, —NH₂, —N(H)(alkyl),—N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl), —N(H)C(O)alkyl,—N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),—N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂, —C(O)N(H)(alkyl),—C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH₂,-alkylN(H)(alkyl), -alkylN(alkyl)₂, -alkylN(H)C(O)NH₂,-alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH,-alkylC(O)Oalkyl, -alkylC(O)NH₂, -alkylC(O)N(H)(alkyl),-alkylC(O)N(alkyl)₂ and R_(c); alternatively, R_(a) and R_(b), togetherwith the nitrogen atom to which they are attached, form a ring selectedfrom the group consisting of heteroaryl and heterocycle; wherein each ofthe heteroaryl and heterocycle is independently substituted with 0, 1, 2or 3 substituents independently selected from the group consisting ofalkyl, alkenyl, alkynyl, cyano, formyl, nitro, halo, oxo, hydroxy,alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl), —SO₂(alkyl),—N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂, —N(H)C(O)N(H)(alkyl),—N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂, —C(O)N(H)(alkyl),—C(O)N(alkyl)₂, cyanoalkyl, formylalkyl, nitroalkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, -alkylNH₂, -alkylN(H)(alkyl),-alkylN(alkyl)₂, -alkylN(H)C(O)NH₂, -alkylN(H)C(O)N(H)(alkyl),-alkylN(H)C(O)N(alkyl)₂, -alkylC(O)OH, -alkylC(O)Oalkyl, -alkylC(O)NH₂,-alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl)₂ and R_(c); R_(c) is aryl,heteroaryl or heterocycle; wherein each R_(c) is independentlysubstituted with 0, 1, 2, 3 or 4 substituents independently selectedfrom the group consisting of halo, nitro, oxo, alkyl, alkenyl, alkynyl,hydroxy, alkoxy, —NH₂, —N(H)(alkyl), —N(alkyl)₂, —SH, —S(alkyl),—SO₂(alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH₂,—N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl)₂, —C(O)OH, —C(O)Oalkyl,—C(O)NH₂, —C(O)N(H)(alkyl), —C(O)N(alkyl)₂, haloalkyl, hydroxyalkyl,alkoxyalkyl, -alkyl-NH₂, -alkyl-N(H)(alkyl), -alkyl-N(alkyl)₂,-alkyl-N(H)C(O)NH₂, -alkyl-N(H)C(O)N(H)(alkyl),-alkyl-N(H)C(O)N(alkyl)₂, -alkyl-C(O)OH, -alkyl-C(O)Oalkyl,-alkyl-C(O)NH₂, -alkyl-C(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl)₂; and nis 1 or
 2. 3. The compound of claim 1 wherein, L is —C(═O) or —C(═S) andR² is alkyl.
 4. The compound of claim 2 wherein, L is —C(═O) or —C(═S)and R² is alkyl.
 5. The compound of claim 1 wherein L is —C(═O) or—C(═S), R² is alkyl, R³ is arylalkyl wherein the aryl moiety of thearylalkyl is substituted with 0 or one R^(3a), and R^(3a) is aryl orheteroaryl.
 6. The compound of claim 2 wherein L is —C(═O) or —C(═S), R²is alkyl, R³ is arylalkyl wherein the aryl moiety of the arylalkyl issubstituted with 0 or one R^(3a), and R^(3a) is aryl or heteroaryl. 7.The compound of claim 1 wherein L is —C(═O) or —C(═S), R² is alkyl, R³is arylalkyl wherein the aryl moiety of the arylalkyl is substitutedwith 0 or one R^(3a) wherein R^(3a) is aryl or heteroaryl and R⁹ is arylor heteroaryl.
 8. The compound of claim 2 wherein L is —C(═O) or —C(═S),R² is alkyl, R³ is arylalkyl wherein the aryl moiety of the arylalkyl issubstituted with 0 or one R^(3a) wherein R^(3a) is aryl or heteroaryland R⁹ is aryl or heteroaryl.
 9. A pharmaceutical composition comprisinga therapeutically effective amount of a compound or combination ofcompounds, or a pharmaceutically acceptable salt form or stereoisomerthereof, and a pharmaceutically acceptable carrier, wherein thecompound, or at least one of said compounds, is selected from the groupconsisting ofmethyl(1S)-1-[({(1R,3S,4S)-3-hydroxy-4-{[(2S)-2-(3-{[6-(1-hydroxy-l-methylethyl)-2-pyridinyl]methyl}-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-5-phenyl-1[4-(2-pyridinyl)benzyl]pentyl}amino)carbony1]-2,2-dimethylpropylcarbamate, and methyl(1S)-1-[({(1S,3S,4S)-4-{[(2S)-2-(3-benzyl-2-oxo-1-imidazolidinyl)-3,3-dimethylbutanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate.